New Journal of ScienceVolume 2014 (2014), Article ID 231418, 36 pageshttp://dx.doi.org/10.1155/2014/231418

Review Article

Protein Kinase C (PKC) Isozymes and Cancer

Jeong-Hun Kang

Division of Biopharmaceutics and Pharmacokinetics, Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan

Received 16 January 2014; Accepted 24 March 2014; Published 4 May 2014

Academic Editor: Eric Hajduch

Copyright © 2014 Jeong-Hun Kang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine kinases, which can be further classified into three PKC isozymes subfamilies: conventional or classic, novel or nonclassic, and atypical. PKC isozymes are known to be involved in cell proliferation, survival, invasion, migration, apoptosis, angiogenesis, and drug resistance. Because of their key roles in cell signaling, PKC isozymes also have the potential to be promising therapeutic targets for several diseases, such as cardiovascular diseases, immune and inflammatory diseases, neurological diseases, metabolic disorders, and multiple types of cancer. This review primarily focuses on the activation, mechanism, and function of PKC isozymes during cancer development and progression.

1. Introduction

Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine kinases that function in numerous different cell types. Based on their structural and activation characteristics, this protein family can be further classified into three subfamilies: conventional or classic PKC isozymes (cPKCs; α, βI, βII, and γ), novel or nonclassic PKC isozymes (nPKCs; δ, ε, η, and θ), and atypical PKC isozymes (aPKCs; ζ, ι, and λ). The activation of cPKCs requires diacylglycerol (DAG) as the primary activator along with phosphatidylserine (PS) and calcium (Ca²⁺) as cofactors of activation. The nPKCs are also regulated by DAG and PS but do not require Ca²⁺ for activation. In the case of aPKCs, their activity is stimulated only by PS and not by DAG and Ca²⁺ [1, 2].

PKC isozymes are involved in multiple signal transduction systems that respond to a variety of external stimulators, including hormones, growth factors, and other membrane receptor ligands. For this reason, PKC isozymes can act as therapeutic targets for several diseases, such as cardiovascular diseases (e.g., atherosclerosis, myocardial fibrosis, cardiac hypertrophy, and hypertension) (for reviews, see [3, 4]), immune and inflammatory diseases (e.g., asthma, arthritis, and hepatitis) [5, 6], neurological diseases (e.g., Alzheimer’s disease and bipolar disorder) [7, 8], and metabolic disorders (e.g., obesity, insulin resistance, hyperglycemia, and hypercholesterolemia) [9–11]. Further, significant work has also explored the activation, mechanism, and function of PKC isozymes in the development and progression of multiple types of cancer, which will be the primary focus of this review.

2. PKC Isozymes and Their Target Proteins

There are five consensus phosphorylation site motifs recognized by PKC isozymes, each of which has an essential basic amino acid (arginine (R) and/or lysine (K)) at the −2 and/or −3 amino-terminal position relative to that of the serine (S) or threonine (T) phosphorylation site. The five motifs are as follows: (R/K)X(S/T), (R/K)(R/K)X(S/T), (R/K)XX(S/T), (R/K)X(S/T)XR/K, and (R/K)XX(S/T)XR/K [12]. A list of target protein substrates for PKC isozymes and their phosphorylation sites are presented in Table S1 (see supplementary materials available online at http://dx.doi.org/10.1155/2014/231418) which has been modified and upgraded from a previous paper [12].

Through target protein phosphorylation, PKC isozymes can directly or indirectly participate in diverse biological phenomena, such as cell cycle regulation (e.g., MARCKS, p53, and p21 (also known as or )), cell adhesion (e.g., adducins and integrins), DNA synthesis and transcription (e.g., transcription factor C/EBP and glycogen synthetase kinase 3β (GSK3β)), cell motility (e.g., RhoA and integrins), apoptosis (e.g., Bad and Bcl-2), drug resistance (e.g., P-glycoprotein (P-gp; also known as MDR1 or ABCB1)), and cell growth and differentiation (e.g., basic fibroblast growth factor (bFGF), epidermal growth factor receptor (EGFR), v-raf-1 murine leukemia viral oncogene homolog 1 (Raf1), and H-Ras) (Table S1).

Further, it is also possible for each PKC isozyme to phosphorylate unique “isozyme-specific” proteins, which can also alter cell function. These types of PKC isozyme-specific substrates or inhibitors may be useful for characterizing intracellular signaling pathways for each PKC isozyme. Although the function of PKC isozyme inhibitors and their clinical applications have been reported by several groups, PKC isozyme-specific inhibitors are very rare, with the majority of the inhibitor studies focusing on the use of bisindolymaleimide (LY333531) and enzastaurin (LY317615) for PKCβ inhibition and antisense oligonucleotides (aprinocarsen (ISIS3521) and ISIS9606) for PKCα inhibition (e.g., for review, see [7, 13–16]). Furthermore, only two PKC isozyme-specific peptide substrates have been identified, peptide 422–426 (RFAVRDMRQTVAVGVIKAVDKK) of eukaryotic elongation factor-1α for PKCδ [17] and Alphatomega peptide (FKKQGSFAKKK) for PKCα [18], both of which have been utilized to characterize PKC isozyme-mediated cellular functions [19–21] and for developing cancer diagnostic [22, 23] or therapeutic tools [24–26].

3. PKC Isozymes and Cancer

In cancer cells, PKC isozymes are involved in cell proliferation, survival, invasion, migration, apoptosis, angiogenesis, and anticancer drug resistance through their increased or decreased participation in various cellular signaling pathways. During cancer cell proliferation and survival; for example, PKC isozymes stimulate survival or proliferation-associated signaling pathways, such as Ras/Raf/MEK/ERK or PI3K/Akt (also known as PKB)/mTOR pathways, but suppress the expression of cancer suppressor-associated or apoptotic signals such as caspase cascade or Bax subfamily (Figure 1). However, the activation statue of PKC isozymes and the downstream signaling cascades can be affected by different internal and external cellular conditions. This is particularly true during short- or long-term 12-O-tetradecanolyphorbol 13-acetate (TPA) treatment, whereby short-term TPA treatment increases PKC activation, but long-term treatment downregulates PKC isozyme function [2, 27].

Figure 1: Multiple signaling pathways, involving PKC isozyme regulation and signal transduction, are affected during cancer. PKC isozymes directly or indirectly participate in diverse biological phenomena in cancer cells such as cell migration, invasion, survival, proliferation, and apoptosis. Casp, caspase; JAK, Janus kinase; Grb2, growth factor receptor-bound protein 2; SOS, son of sevenless homolog; also see abbreviations in the text. Black arrows indicate activation cascade, while red arrows are used to show the inhibition cascade.

Furthermore, the expression patterns and functions of PKC isozymes in cancer cells largely depend on the type of cancer being investigated; however, the mechanism is not clear. For example, PKCδ acts as an antiapoptotic regulator in chronic lymphocytic leukemia (CLL) but as a proapoptotic regulator in acute myeloid leukemia (AML) (see Section 3.10. Myeloid and lymphocytic leukemia). PKCα shows proliferative functions in several types of cancer but has antiproliferative functions in colon cancer cells (see Section 3.3. Colon cancer). Importantly, PKC isozymes that are specifically overexpressed in certain types of cancer can be used as diagnostic or therapeutic targets. Thus, understanding the role and expression of individual PKC isozymes in each type of cancer may help to elucidate important cues for discovering novel drugs and for developing diagnostic or therapeutic tools. This section further discusses PKC isozymes and their roles in multiple types of cancer cells as summarized in Table 1.

Table 1: PKC isozymes and their roles in multiple types of cancer cells.

Cancer types
PKC isozymes
Roles of PKC isozymes
References

Bladder cancer
PKCα
Cell proliferation and anticancer drug resistance
[31, 33]

PKCδ
Cell motility
[39]

Breast cancer
PKCα
Cell proliferation and metastasis, antiapoptosis, antiestrogen resistance
[40, 42, 43, 45, 50, 53]

PKCε
Cell metastasis and antiapoptosis
[63, 65, 67]

PKCη
Cell growth, survival, and antiapoptosis
[68–70, 72]

PKCζ
Cell metastasis
[74]

PKCδ
Cell survival, migration, invasion, proliferation, antiestrogen resistance, and proapoptosis
[80, 83, 84, 86, 88, 90, 92, 94, 97]

Colon cancer
PKCα
Antiproliferation and anticancer drug resistance
[110–112, 119, 120]

PKCβII
Cell proliferation and invasion when cells overexpressing PKCβII are used
[123, 124, 130]

PKCι
Carcinogenesis
[134, 135]

PKCζ
Antiproliferation, differentiation, and proapoptosis
[136–138]

PKCδ
Cell proliferation and pro- and antiapoptosis
[142, 144, 145, 147, 152, 153]

Gastric (stomach) cancer
PKCα
Cell proliferation and antiapoptosis
[158, 160, 161]

PKCβI
Antiapoptosis
[164, 165]

PKCδ
Cell invasion and proapoptosis
[170–172]

Gastrointestinal stromal tumor (GIST)
PKCθ
Cell proliferation and antiapoptosis
[175]

Glioma
PKCα
Cell proliferation, survival, invasion, migration, antiapoptosis, and anticancer drug resistance
[189, 190, 192, 196, 197, 204]

PKCε
Cell survival, invasion, migration, and antiapoptosis
[206, 207, 209]

PKCζ
Cell proliferation, survival, invasion, and migration
[212–214, 216, 217]

PKCι
Cell proliferation, survival, and invasion
[218, 220, 221, 223]

PKCη
Cell proliferation and antiapoptosis
[224, 225, 227]

PKCδ
Cell proliferation, invasion, and pro-/antiapoptosis
[228–231, 240–242]

Head and neck cancer
PKCα
Cell growth and survival
[245–247]

PKCε
Cell proliferation and invasion
[248, 249]

PKCζ
Cell proliferation, invasion, and migration
[250, 251, 253]

PKCι
Cell proliferation and antiapoptosis
[256, 257]

Liver cancer (hepatocellular carcinoma)
PKCα
Cell growth, invasion, and migration
[269, 271, 272, 276, 280]

PKCε
Cell growth and migration
[276, 285]

PKCδ
Cell invasion and migration
[282]

Lung cancer
PKCα
Cell proliferation, metastasis, and antiapoptosis
[288, 291, 293]

PKCε
Cell proliferation, metastasis, and antiapoptosis
[299, 301, 303–305]

PKCι
Cell growth, survival, and invasion
[307, 308, 311, 313]

PKCη
Cell metastasis and antiapoptosis
[321, 322]

PKCδ
Cell survival, invasion, migration, and antiapoptosis
[323–326]

Melanoma
PKCα
Cell survival, invasion, and migration
[336, 337]

PKCε
Antiapoptosis
[342–344]

PKCδ
Cell metastasis
[347, 348]

Myeloid and lymphocytic leukemia

    Acute lymphocytic leukemia (ALL)
PKCα
Anticancer drug resistance
[367]

    Chronic lymphocytic leukemia (CLL)
PKCβ
Cell survival
[357]

    Acute myeloid leukemia (AML)
PKCβII
Cell proliferation, survival, and antiapoptosis
[351, 359, 360, 363]

    Chronic myeloid leukemia (CML)
PKCδ
Cell survival
[364, 365]

PKCα
Antiapoptosis
[370, 376, 379]

PKCδ
Proapoptosis
[382–386]

PKCβII
Cell proliferation and survival
[368]

PKCδ
Proapoptosis
[374, 375]

Ovarian cancer
PKCα
Cell proliferation and invasion
[389, 390]

PKCι
Cell proliferation
[392, 393]

PKCζ
Proapoptosis
[394]

Pancreatic cancer
PKCα
Cell differentiation, migration, and antiapoptosis
[397, 398, 400, 401]

PKCζ
Cell survival and metastasis
[405, 407, 408]

PKCι
Angiogenesis and cell metastasis
[409, 411]

PKCβI
Cell migration and antiapoptosis
[412]

PKCδ
Cell growth and anticancer drug resistance
[416, 417]

Prostate cancer
PKCα
Cell growth, migration, invasion, angiogenesis, and pro-/antiapoptosis
[425, 428–432, 436]

PKCε
Cell growth, survival, invasion, antiapoptosis, and anticancer drug resistance
[438–441, 443–445, 447]

PKCζ
Cell proliferation
[456]

PKCη
Antiapoptosis
[457]

PKCβII
Cell growth and angiogenesis
[458]

PKCδ
Cell migration, invasion, angiogenesis, and proapoptosis
[420, 459, 460, 468–470]

Renal cell carcinoma (kidney cancer)
PKCα
Cell invasion
[475]

PKCε
Cell growth, invasion, and migration
[475, 479]

PKCδ
Cell migration and invasion
[482–484]

Thyroid cancer
PKCα
Cell survival
[485, 486]

PKCε
Cell survival and pro-/antiapoptosis
[492–494]

PKCδ
Antiproliferation and cell migration
[497–499]

3.1. Bladder Cancer

PKCα, βI, βII, δ, ε, η, and ζ have all been detected in bladder cancer cells and tissues. PKCβI, βII, δ, and η are found primarily in low-grade and low-stage cancers and decrease with increasing cancer stage and grade. However, PKCα and ζ show the opposite expression pattern, increasing in levels as the cancer progresses [28–30], and are associated with more aggressive bladder cancer. Patients with a higher membrane/cytosol ratio of PKCα show a shorter recurrence-free period than patients with a lower membrane/cytosol ratio after treatment with the anticancer drug adriamycin. Further, transfection of PKCα into bladder cancer cells increases resistance against adriamycin [31]. It has also recently been shown that the phosphoinositide-specific phospholipase Cε (PLCε), an effector protein of Ras and Rap [32], induces the proliferation of human bladder cancer cell line BIU-87 through the activation of PKCα [33]. However, the PKCα-mediated proliferation of bladder cancer cells can be repressed. T24 cells treated with the PKCα/β inhibitor GO6976, for example, show G0/1 arrest and reduced proliferation [34]. Moreover, addition of this inhibitor to bladder cancer cells 5637 and T24 results in more efficient inhibition of cell migration and invasion and greater promotion of cell-cell and cell-matrix junctions than those achieved using the PKCα inhibitor Safingol, which has similar but less pronounced effects [35].

Similarly, in T24 cells, the binding of hyaluronic acid (HA) fragments to CD44 can activate the NF-κB pathway through not only PKCζ, but also Ras and IκB kinases 1 and 2 [36]. Researchers have speculated that these signaling pathways may be related to cancer cell migration and invasion [37] or survival and antiapoptosis [38].

Activation of PKCδ and c-Jun N-terminal kinase (JNK) results in the depletion of growth factors, which reduces cell-cell adhesions, promotes reactive oxygen species (ROS) production, and increases T24 cell motility and scattering [39].

3.2. Breast Cancer

In breast cancer cells, several PKC isozymes, such as PKCα, β, δ, ε, ζ, η, and θ participate in cell proliferation, differentiation, survival, and apoptosis. Although PKCα is very important for controlling the proliferation of breast cancer cells through the activation of extracellular signal-regulated kinase (ERK) [40] and telomerase [41], many research efforts focus on its function in metastasis and drug resistance. PKCα expression contributes to the metastasis of breast cancer cells through upregulation of activity of matrix metalloproteinases (MMPs) (e.g., MMP-9) [42–44], urokinase-type plasminogen activator (uPA) [44, 45], NF-κB [42], and osteopontin receptor αvβ3 [46], as well as through increasing the cell surface levels of C-X-C chemokine receptor type 4 (CXCR4) (also known as CXCL12), which is also associated with lung metastasis of breast cancer cells [42]. During tyrosine kinase receptor ErbB2 (also known as HER2, CD340, or neu)-mediated breast cancer cell invasion, ErbB2 upregulates PKCα through c-Src kinase, leading to upregulation of uPA and uPA receptors that facilitate cell invasion and migration [44, 45].

Antiestrogen hormonal therapy (e.g., tamoxifen (TAM)) is effective for estrogen receptor α (ERα) positive/progesterone receptor positive breast cancers; however, resistance to this treatment is one of major issues to be overcome in breast cancer therapy. Breast cancer antiestrogen resistance is mainly due to the loss of ERα, but it can still occur when ERα is still present [47–49]. Further, research has indicated that PKCα may be a critical factor in breast cancer antiestrogen resistance. PKCα and ERα expression are inversely related [47] and PKCα is positively correlated with triple-negative breast cancers, which show no expression of ERs, progesterone receptors, or ErbB2 [50, 51]. Breast cancer cells with overexpression of PKCα also show high resistance for TAM treatment and hormone (e.g., estrogen)-independent growth [52–55], but inhibition of PKCα induces TAM sensitivity [53–55]. The underlying mechanism of breast cancer antiestrogen resistance also includes ERK2 activation by PKCα [48]. In addition, PKCα expression in breast cancer cells inhibits heregulin-induced apoptosis through the upregulation of Bcl-2 and downregulation of caspase-7 [56]. PKCα also participates in multidrug resistance (MDR) in breast cancer cells [57, 58]. Overexpression of PKCα in MCF-7 cells alters β5- and β3-integrin expression by translational and posttranslational mechanisms, respectively, leading to the increased metastatic capacity of cancer cells [59]. Thus, PKCα expression in breast cancer cells may be closely associated with poor prognosis and survival [49, 60].

In a previous study, activation of PKCβI and βII in MCF-7 cells promoted growth and enhanced expression of cyclin D1, which is a regulator of G₁ to S phase transition in mammalian cells [61]. Contrary to this, Grossoni’s group has reported that overexpression of PKCβ1 in the breast cancer cell line LM3 actually reduces cell growth and expression of the metastasis-related proteases, uPA, and MMP-2 [62]. Thus, further research is required to decipher the true function of the PKCβ1 and PKCβ1I isozymes in breast cancer.

For PKCε, downregulation along with the overexpression of microRNA miR-31 appears to reduce oncogenic NF-κB activity and enhance apoptosis and chemo- and radiosensitivity of breast cancer cells. These responses are caused by impaired expression of antiapoptotic Bcl-2 protein [63]. However, when PKCε activation occurs through HA binding to its receptor CD44, it increases the Nanog-mediated miR-21 production in MCF-7 cells. This process inhibits production of the tumor suppressor protein PDCD4, while enhancing the expression of antiapoptosis genes and anticancer drug resistance in MCF-7 cells [38]. In addition, activation of glucocorticoid receptor (GR) by stimulating GR agonists, such as hydrocortisone and dexamethasone, can inhibit p53-dependent apoptosis of breast cancer cells through an increase in the levels of PKCε messenger RNA (mRNA) and protein [64]. PKCε can also protect breast cancer cells from major death factor tumor necrosis factor α (TNFα)-induced cell death through DNA-dependent protein kinase-mediated Akt activation [65], Akt-dependent murine double minute 2 activation, and p53 downregulation [66]. Further, PKCε-induced polymeric fibronectin assembly is required for the pulmonary metastasis of breast cancer cells [67].

Upregulation of PKCη in malignant breast cells is also associated with cancer cell growth and survival [68], likely through hormone-dependent cell growth pathways [69]. PKCη expression in the membrane of breast cancer cells after chemotherapy tends to predict a poor patient prognosis [70]. PKCη-mediated inhibition of proapoptotic JNK activity protects breast cancer cells from chemotherapy and irradiation therapy [71]. In addition, overexpression of PKCη delays TNF-induced cell death in MCF-7 cells by reducing the activation of caspase-8 and caspase-7 [72]. In spite of low levels of PKCη being found in most invasive breast cancer lesions (75%), invasive cancers containing high PKCη are associated with positive lymph node status [73].

PKCζ-mediated hepatocyte growth factor (HGF) activation increases CXCR4 expression, resulting in breast cancer cell metastasis [74]. PKCζ also stimulates estrogen-mediated breast cancer cell growth by stabilizing steroid receptor coactivator-3 (SRC-3; also known as AIB1, ACTR, pCIP, RAC3, or TRAM-1) [75]. On the other hand, overexpression of PKCζ can inhibit growth factor-mediated Akt phosphorylation and activation, namely, through feedback inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade [76].

Accumulation of PKCθ-activated Fra-1 in invasive, ER-negative breast cancer cells has been associated with increased cell invasion and migration [77]. In addition, PKCθ-mediated Akt activation inhibits forkhead box class-O 3a (FOXO3a), which is the transcriptional activator of ERα promoter B and its targets, ERα and , and also induces c-Rel activation, which has been associated with the early development of breast cancer cells. These signaling changes by Akt activation result in proliferation, survival, and invasion of breast cancer cells [78].

PKCδ isozyme shows both prosurvival and proapoptotic functions in breast cancer cells. PKCδ expression is significantly higher in ER-positive than ER-negative breast cancers and is associated with poor patient survival [79]. PKCδ promotes survival of breast cancer cells through the inhibition or activation of several signaling pathways, such as inhibition of TNF-related apoptosis-inducing ligand (TRAIL)-induced caspase activation [80, 81], inhibition of Notch1 intracellular domain-dependent transcriptional activity [82], reduction of anticancer drug taxol-induced monocyte chemoattractant protein-1 expression [83], and activation of Akt and NF-κB [84, 85]. PKCδ also shows increased antiestrogen resistance in estrogen- and TAM-induced MCF-7 cells through the activation of Akt and mitogen-activated protein kinases (MAPKs) [86]. In ER negative MDA-MB-231 breast cancer cells, PKCδ supports their survival by inhibiting ERK1/2 activation and increasing the levels of ERK1/2 phosphatase MKP3 and its regulator, E3 ubiquitin ligase Nedd4 [87].

On the other hand, proapoptotic effects of PKCδ in breast cancer cells have also been reported. Exposure of MCF-7 cells to ultraviolet (UV) light increases apoptosis of cells through PKCδ-dependent phosphorylation of acid sphingomyelinase [88]. Furthermore, sangivamycin, an antiproliferative agent, induces mitochondria-mediated apoptotic cell death of MCF-7/ADR cells by increasing JNK phosphorylation and cleavage of lamin A and poly (ADP-ribose) polymerase. These apoptotic responses have all been identified as being PKCδ-dependent [89]. Treating MCF-7 cells with inositol hexaphosphate (IP₆) causes an increase of PKCδ associated with a decrease of ERK1/2 and Akt activation. This IP₆-mediated PKCδ activation enhances upregulation of and hyperphosphorylation of retinoblastoma protein (pRb or Rb), resulting in an increase in apoptosis (G₁ arrest) of MCF-7 cells [90]. PKCδ-dependent inhibition of ERK1/2 and upregulation of JNK also lead to G₁ arrest in SKBR3 breast cancer cells after phorbol-myristate-acetate (PMA; note that a common alternative name for PMA is TPA) treatment [91].

In addition, PKCδ acts as a proliferative signal in breast cancer cells. PKCδ elevates cell proliferation in ErbB2-positive breast cancer cells via c-Src and ERK activation [92]. The inflammatory mediator bradykinin (BK) is required for the PKCδ/ε/Akt/ERK1/2 signaling complex utilized to mediate MCF-7 cell proliferation [93]. In estrogen-dependent breast cancer cells, TPA-mediated PKCδ activation leads to activation and nuclear translocation of ERα and enhanced ER-dependent reporter gene expression thereby suggesting a role of PKCδ as a proproliferative factor [94]. Cell proliferation requiring estrogen (e.g., 17-β-estradiol) also needs ERK1/2 activation through the HRG/HER-2/PKCδ/Ras pathway [95]. Interestingly, TPA-induced PKCδ activation in ER negative cells shows a different pattern compared to ER positive breast cancer cells. The increase in PKCδ expression is significantly higher in ER positive MCF-7 cells than in ER negative MDA-MB-231 cells, leading to higher levels of cyclin dependent kinase (Cdk) inhibitor in MCF-7 cells [96].

In addition to its proapoptotic, prosurvival, and proliferative functions, PKCδ also plays a critical role in breast cancer cell migration and invasion. In highly metastatic breast cancer cell lines (e.g., MDA-MB-231 and C3L5), expression of PKCδ efficiently increases cell migration and invasion by inhibiting the small GTPase Cdc42 [97]. TPA-induced MMP-9 activation and migration of breast cancer cells are also stimulated by the PKCδ/ERK/c-Jun/activator protein-1 signaling pathway, but quercetin and kalopanaxsaponin can be used to block these signaling pathways [98, 99]. Moreover, platelets can promote invasion of MCF-7 cells through the activation of PKCδ and upregulation of MMP-9 [100]. In contrast, Jackson’s group has demonstrated that PKCδ suppresses MMP-9 secretion and breast cancer cell survival and migration [101].

3.3. Colon Cancer

PKCα, β, δ, ε, and ζ are found in both rat and human colonic mucosa, while PKCη is detected in human colonic mucosa only [102]. There is no difference in the levels of PKCα, δ, and ε mRNA between normal mucosa and human colon adenocarcinoma, but the levels PKCβ and η mRNAs are significantly lower in human colon adenocarcinoma than in normal mucosa. The reduction of PKCβ and η mRNA occurs early in the multistage process of colon carcinogenesis [103]. Western blotting analysis, on the other hand, has indicated that expression of PKCβ and ε protein is significantly decreased in colon cancer tissues, while PKCα and ζ show no significant difference in expression between normal mucosa and colon cancer tissues [104].

In a recent study, colon epithelial cells (CECs) showed high levels of PKCε with no TRAIL expression, but luminal CECs show the opposite result. This support previous results indicating that PKCε is required for TRAIL-induced differentiation of the colorectal cancer cell line HT29 [105]. Further, activated PKCε is also necessary for proteinase-activated receptor 1 (PAR1)-mediated HT29 cell migration and matrix adhesion [106].

Although the levels of PKCα are similar between normal and cancerous colon tissue, increasing evidence shows that PKCα does participate in growth arrest [107, 108] and cancer suppression in the intestine epithelium [109–113]. Suppression of cell growth in colon cancer cells by PKCα is thought to occur through the regulation of EGFR signaling [110]; ERK-mediated inhibition of the inhibitor of DNA binding 1, a proproliferative factor [112]; downregulation of β-catenin and its target genes cyclin D1 and c-Myc [111, 113]; and PKCα-mediated phosphorylation of retinoic acid-related orphan nuclear receptor α, which downregulates the Wnt/β-catenin signaling [114]. In contrast to these results, a recent study has suggested that PKCα activation is involved in the activation of ERK1/2/NF-κB through the tissue factor/VIIa/PAR2 pathway and this signaling pathway leads to enhanced proliferation, migration, and survival for the colon cancer cell line SW620 [115].

Alternately, PKCα can also enhance cell adhesion and anticancer resistance through a different signal pathway than that used during antiproliferation. High migratory activity of colon cancer cells is related to high PKCα and low E-cadherin expression [116]. PKCα also regulates transforming growth factor (TGF)-β1-induced expression of the matrix adhesion molecules, fibronectin and laminin, leading to the induction of E-cadherin [117, 118]. In addition, PKCα can induce P-gp-mediated MDR in human colon cancer cells [119–121]; thus, downregulation of PKCα may increase the sensitivity to anticancer agents [122].

The low levels of PKCβ in colon cancer cells allow transgenic mice and cells stably expressing PKCβ to be used to investigate the role of PKCβ in colon cancer cells. In transgenic PKCβII animals and PKCβII-expressing cell lines, the presence of PKCβII results in hyperproliferation of intestinal epithelial cells and enhanced cancer formation after exposure to azoxymethane, a potent carcinogen used to induce colon cancer [123–126]. These responses are achieved through the reduction of TGF-β receptor type II expression and associated growth inhibition [124, 127], activation of Wnt/adenomatous polyposis coli/β-catenin proliferative signaling [123], and reduction of cyclooxygenase type 2 (Cox-2) expression [127]. Overexpression of PKCβII also induces invasion in intestinal epithelial cells through a Ras/PKCι/Rac1/MAPK kinase (MEK)-dependent signaling pathway [128] and represses apoptosis at the luminal surface in transgenic rats [129].

PKCβI is activated in the presence of secondary bile acids (e.g., deoxycholic acid, lithocholic acid, and ursodeoxycholic acid) in colon cancer tissues [104]. Furthermore, the human colon adenocarcinoma cell line HT-29 stably expressing PKCβ1 shows high resistance to TNFα- and paclitaxel-induced apoptosis [130]. Overexpression of PKCβI and βII in differentiated colon carcinoma HD3 cells blocks their differentiation but increases their proliferation through p57 MAPK activation [131, 132]. These data suggest that PKCβ inhibitors (e.g., enzastaurin) may be efficient for the prevention of colon cancer because PKCβI and II appear to be involved in carcinogen-induced colon cancer initiation and progression [122, 124, 125, 133].

PKCι is also required for Ras- and azoxymethane-induced colon carcinogenesis [134, 135], but unlike PKCβII, PKCι functions mainly in the later stage of azoxymethane-induced colon carcinogenesis and is essential for mutant adenomatous polyposis coli (APC)-mediated carcinogenesis [135].

Like PKCα, PKCζ protein expression does not differ between normal and cancerous tissues, but PKCζ does appear to be associated with the inhibition of colon cancer cell growth and enhancement of differentiation and apoptosis [136, 137]. In a recent study, the loss of PKCζ resulted in an increase in intestinal carcinogenesis, upregulation of two metabolic enzymes, 3-phosphoglycerate dehydrogenase and phosphoserine aminotransferase-1, and inhibition of caspase-3 activation. Thus, colon cancer patients with low levels of PKCζ show a significantly poorer prognosis, compared with patients with higher levels [138]. In contrast, PKCζ stably depleted SW480 colon cancer cells by decreasing cell proliferation, expression of Wnt target gene c-Myc, and tumorigenic activity in grafted mice [139]. Dexniguldipine hydrochloride (B8509-035) also suppresses the growth of HT-29 cells through the inhibition of PKCζ expression [140]. Similar to PKCβ, PKCζ could likely be an efficient target for chemoprevention of colon cancer [141]. Thus, further research is needed to understand the true function of PKCζ in colon cancer.

In colon cancer cells, PKCδ can inhibit cell growth and proliferation by mediating changes in several cellular signaling pathways by enhancing phosphorylation of APC [142], p53 expression [143, 144], and activity [144] and by reducing β-catenin stabilization [140] and cyclins (e.g., D1, D3, and E) [145, 146].

PKCδ expression may also act as a proapoptotic regulator in colon cancer cells. This regulation is required for G₀/G₁ arrest [147], inhibition of anchorage-independent growth [147], and enhanced Bax levels [146]. The apoptotic pathway utilized by PKCδ also appears to be independent of caspase-3 [148]. In contrast, PKCδ may have antiapoptotic functions as well. For example, apoptosis is prevented by the PKCδ/NF-κB/cIAP-2 pathway [149] and activation of the FLICE-like inhibitory protein [150].

Furthermore, PKCδ is involved in colon cancer cell migration and invasion through activation of the metastasis enhancing protein KITENIN [151], KIT-SCF activation, PKCδ-induced KIT recycling [152], phosphorylation of the mRNA-binding protein HuR at serine 318 [153], and stimulation of Nox1-dependent superoxide production [154].

3.4. Gastric (Stomach) Cancer

3.4.1. General Gastric Carcinoma

Overexpression of PKCα in human gastric carcinoma is significantly correlated to poor prognosis and clinicopathological parameters, such as histologic type, depth of invasion, pathologic stage, and distant metastasis [155, 156]. In the vincristine-induced MDR human gastric cancer cell line SGC7901/vincristine, higher levels of PKCα are found compared with those detected in untreated (i.e., not MDR) SGC7901 cells [157]. Thus, inhibition of PKCα may enhance antiproliferative and proapoptotic signaling in gastric cancer cells thereby increasing the therapeutic efficacy for gastric cancer [158–161]. In contrast, addition of TPA to gastric cancer cells enhances PKCα-mediated cell apoptosis [162, 163].

After addition of indomethacin, a nonsteroidal anti-inflammatory drug, into gastric cancer cells, PKCβI, but not PKCβII, acts as a mediator of cancer cell survival, and its overexpression, which is associated with overexpression of promotes activation of antiapoptotic mechanism [164, 165]. On the other hand, addition of the PKCβ inhibitor enzastaurin into gastric cancer cells induces apoptosis through the ribosomal S6 kinase and Bad pathways [166].

Gastric adenocarcinoma exhibits loss of PKCζ [167], while overexpression of PKCλ/ι can be a prognostic factor for gastric cancer recurrence [168]. However, low PKCλ/ι expression along with high expression of kidney and brain protein (KIBRA; also known as WWC1), which is a scaffold protein containing aPKC-binding domains, has also been shown to have detrimental results, as they are correlated with invasion and poor prognosis in gastric cancer [169].

PKCδ positively controls cisplatin- and sphingosine-induced cell death in MKN28 cells. The former is correlated with overexpression of p53 and the latter with enhanced SDK and caspase-9 production [170, 171]. In addition, enhanced PKCδ expression and phosphorylation can increase cell motility and invasion by cooperating with the Smad-dependent TGF-β1 pathway and integrin (α2 or α3) expression and activation [172].

3.4.2. Gastrointestinal Stromal Tumor

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, being primarily found in the stomach and small intestine. The five-year survival rate of patients with KIT-negative GIST is lower than that of patients with KIT-positive GIST (KIT is also known as CD117, proto-oncogene c-kit, tyrosine-protein kinase Kit, or mast/stem cell growth factor receptor) [173]. PKCθ expression is observed in GISTs but is undetectable in other mesenchymal tumors, including non-GIST soft tissue sarcomas [174]. PKCθ knockdown in KIT-positive GISTs leads to inhibition of PI3K/Akt signaling, upregulation of the cyclin-dependent kinase inhibitors p21 and p27, and induction of antiproliferative and apoptotic factors [175]. Thus, PKCθ is recognized as a useful biomarker for the diagnosis of KIT- and/or DOG1-negative GISTs [176–178], while it shows high sensitivity toward KIT-positive GISTs [174, 179, 180]. However, it should be noted that these sensitivity and specificity of PKCθ toward KIT-negative GISTs were not observed in all studies [173].

3.5. Glioma

Among gliomas, astrocytomas are the most common and are classified in four prognostic grades: pilocytic astrocytoma (grade I), low-grade astrocytoma (grade II), anaplastic astrocytoma (grade III), and glioblastoma (grade IV). Grade III and IV are considered to be the most rapidly progressive, invasive malignant gliomas [181]. In the rat malignant glioma cell line C6, one study has reported the detection of PKCα, δ, ε, and ζ [182], but González’s group did not detect PKCζ in these cells [183]. Moreover, PKCα, γ, δ (very low levels), ε, and ζ have been identified in multiple human malignant glioma cell lines (e.g., A172, A2781, U87, U138, U373, and A1235) and tissues [184–186]. For PKCβ, there are conflicting reports, some which indicate PKCβ detection [186, 187], while others show no PKCβ expression [184, 185, 188]. In TPA-treated glioma cells, PKCα is translocated from the cytosolic fraction to the membrane following short-term exposure but is downregulated following long-term exposures [182, 185].

Higher levels of PKCα in malignant gliomas compared to low-grade astrocytomas result in enhanced proliferation and decreased apoptosis for the malignant gliomas [186]. PKCα-mediated ERK1/2 activation is also required for the proliferation and survival of glioma cells [189]. Moreover, PKCα acts as a signaling intermediate between EGFR and mammalian target of rapamycin (mTOR) in glioma cells; the activation of which leads to Akt-independent proliferation of glioma cells [190]. Interestingly, PKCα protein, but not its activity, is essential for glioma cell proliferation and survival. These results mean that the use of adenosine triphosphate (ATP) competitive inhibitors to treat glioma will be less efficient [191]. In addition, increased expression of glutamate transporters, also known as excitatory amino-acid transporters, leads to prolonged survival and reduced tumor growth in glioma-bearing animals [192]. Further, PKCα is involved in the activation and redistribution of glutamate transporters [183, 193, 194]. However, there is a report that inhibition of PKCα and ε has no effect on proliferation of glioma cells thereby suggesting no therapeutic benefit of PKCα in regard to proliferation prevention [195].

Cooperation of inhibition of PKCα and suppression of glutathione S-transferase P1, which is associated with anticancer drug resistance, can efficiently increase the apoptosis of glioma cells by the anticancer drug cisplatin [196]. Combination of endostatin, an inhibitor of angiogenesis, and PKCα inhibition significantly increases the survival of malignant glioma-bearing animals [197]. Reduction of the antiapoptotic protein Bcl-XL is also involved in glioma cell death through the inhibition of PKCα [198]. However, aprinocarsen, an antisense oligonucleotide against PKCα, shows no clinical benefit in patients with recurrent high-grade astrocytomas [199].

There are many reports proving a close relationship between PKCα expression and high invasion and migration of malignant glioma cells [200–204]. As mentioned above, translocation of PKCα from the cytosolic fraction to the glioma cell membrane after TPA treatment increases ERK/NF-κB-dependent MMP-9 activation and cell migration [200]. PKCα-induced phosphorylation and downregulation of low-density lipoprotein receptor-related protein stimulate the secretion of uPA and the invasion of glioma cells into the surrounding normal brain tissue [201]. Furthermore, invasion and migration of glioma cells involve several signaling pathways such as PKCα-mediated N-cadherin cleavage [202], increased motility by PKCα-mediated NG2 phosphorylation at Thr-2256 [203], and PKCα or ε/SRF-mediated RTVP-1 expression [204].

PKCε also appears to be overexpressed in malignant glioma cell lines and tissues (grades III and IV) [184–186, 205]. Its overexpression in glioma cells inhibits proteasome inhibitor- and TRAIL-induced apoptosis and increases cell survival [206, 207]. Signal transducers and activators of transcription 3 (Stat3) activation by PKCε in glioma cells also stimulate cell invasion. These responses are found in not only glioma, but also several additional types of human cancer cells, including prostate, skin (melanoma), bladder, colon, lung, pancreatic, and breast [208]. Furthermore, galectin-1, a homodimeric adhesion molecule, is linked with the trafficking of β1-integrin, which is controlled by a PKCε/vimentin-dependent pathway. These molecular responses are important for glioma cell migration [209]. In PMA-induced adhesion and migration of glioma cells, PKCε shows different response compared to PKCα in regard to ERK activation. PKCε induces the activation of ERK at focal adhesions, while PKCα induces the activation of nuclear ERK [210]. Importantly, inhibition of PKCε has been shown to block the proliferation of glioma cells [211].

PKCζ may also be a therapeutic target for treating gliomas because of its involvement in proliferation, invasion, and migration of glioma cells. Phosphorylated PKCθ/δ/β1-integrin and PKC ζ/β1-integrin complexes are stimulated following radiation exposure, resulting in enhanced radioresistance of glioma cells [212]. Further, downregulation of uPA receptor and cathepsin B using small hairpin RNA efficiently disrupts these complex formations [212]. In addition to β1-integrin activation [212, 213], PKCζ is involved in glioma cell migration and invasion by controlling its interaction with ZIP/p62 [214] and MMP-9 expression [213, 215]. Furthermore, PKCζ also plays a key role in the proliferation of glioma cells, which in C6 cells is modulated through P2Y₁₂ receptor signal transduction by the RhoA-dependent PKCζ/Raf1/MEK/ERK pathway [216]. Activation of PKCζ/p70S6K pathway by muscarinic acetylcholine receptor also increases carbachol-induced DNA synthesis and proliferation in 1321 N1 astrocytoma cells [217].

Although previous studies have failed to show the existence of PKCι in normal glioma cells [184–186], PKCι is abundant in all malignant gliomas, especially in highly proliferative glioma cell lines, such as T98G and U-138MG [218]. Proliferation of glioma cells is controlled through the PI3K/PKCι/Cdk7/Cdk2-mediated pathway [219, 220]. Inactivation of Bad and disruption of the Bad/Bcl-XL dimer by PKCι also enhance glioma cell survival [221]. Furthermore, PKCι participates in antiapoptosis of glioma cells through the downregulation of p38 MAPK signaling [222] and glioma cell invasion and motility through the repression of actin stress fiber formation by RhoB [223].

Although PKCη shows low detection rates in glioma cell lines [195], its potential as a therapeutic target for glioma has been demonstrated. PKCη expression enhances glioma proliferation and cell growth through MEK1/2/ERK1/2/Elk-1 [224] or Akt/mTOR pathways [225]. PKCη also plays an important role in rapamycin-insensitive cell proliferation [226]. Moreover, PKCη expression increases glioma cell resistance to UV- and γ-irradiation-induced apoptosis through the downregulation of caspase-9 activation [227].

PKCδ phosphorylation at tyrosine 311 (e.g., by c-Ab1 tyrosine kinase) and 332 (e.g., by c-Src tyrosine kinase) is an important process during caspase-3-dependent cleavage of PKCδ, a process that can enhance apoptosis of glioma cells [228, 229]. For example, PKCδ phosphorylation at tyrosine 332 by c-Src increases the sensitivity of glioma cells to TRAIL and cisplatin [228]. Moreover, different locations of PKCδ expression in glioma cells can influence its proapoptotic and antiapoptotic effects. Cytosolic PKCδ increases p38 phosphorylation and decreases Akt phosphorylation and expression of X-linked inhibitor of apoptosis protein (XIAP), while nuclear PKCδ increases JNK activation, all of which result in enhanced apoptotic effects. However, PKCδ localized in the endoplasmic reticulum leads to antiapoptosis of glioma cells [230]. Phosphorylation at tyrosine 155 and cleavage of PKCδ increase its translocation to the endoplasmic reticulum and ability to block TRAIL-induced apoptosis [231]. Phosphorylation of PKCδ at tyrosine 52, 64, and 155 is associated with the virulent strain of Sindbis virus neurovirulent and can induce glioma cell apoptosis [232]. Phosphorylation of PKCδ at 64 and 287 is also essential for the apoptotic effect observed after etoposide treatment [233–235]. Furthermore, penta-acetyl geniposide-induced apoptosis requires the interaction of activated neutral sphingomyelinase and p75, which is mediated by activated PKCδ [236, 237]. PKCδ-mediated ROS production has also been indicated to increase paraquat (1,1′-dimethyl-4,4′-bipyridinium)-induced glioma cell death [238]. In a recent study, however, activation of PKCδ in patient-derived glioma cells increased the fractionated-radiation-induced expansion of glioma-initiating cells and resistance to cancer treatment [239].

EGFR transactivation by enhanced PKCδ/c-Src signaling pathway stimulates glioma cell proliferation [240]. Activation of PKCδ also stimulates glioma cell invasion and motility by EGF-induced translocation of sphingosine kinase 1 and upregulation of plasminogen activator inhibitor-1 [241] as well as tenascin-C-induced upregulation of MMP-12 [242].

3.6. Head and Neck Cancer

Head and neck cancers occur mainly in the squamous cells of the oropharynx, oral cavity, hypopharynx, and larynx and are often referred to as head and neck squamous cell carcinomas (HNSCCs) [243, 244].

PKCα activation increases DNA synthesis and cell growth by activating ERK and cyclin E synthesis, but miR-105 acts as an inverse regulator for both DNA synthesis and cyclin E protein expression [245]. In chemokine receptor 7-positive HNSCC cells, PKCα is required for activation and nuclear translocation of NF-κB induced by chemokine (C-C motif) ligand 19, resulting in enhanced cell survival [246, 247].

PKCε, on the other hand, is involved in cell proliferation, DNA replication, and invasion in HNSCC cells [248, 249]. These cellular functions can be blocked by miR-107, which can inhibit PKCε activation [249]. PKCε-mediated HNSCC cell invasion and motility can be induced through activation of RhoA and C [248].

PKCζ activation by phosphorylation at tyrosine 417 plays an important role in EGF-mediated ERK activation, DNA synthesis, and cell proliferation in HNSCCs [250, 251], while depletion of PLC-γ1 or PI3K enhancer may abolish EGF-mediated SCC cell proliferation [252]. Furthermore, inhibition of PKCζ can reduce epithelial-mesenchymal transition (EMT), invasion, and migration of oral SCC mediated by the loss of interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) and E-cadherin. Oral SCC patients with reduced IFIT2 levels show higher rates of metastasis and poorer prognoses compared with oral SCC patients with enhanced IFIT2 levels [253]. In addition, PKCα, βI, δ, and ζ are involved in the regulation of telomerase activity by direct or indirect phosphorylation of telomerase proteins, and PKCζ is also a key regulator in nasopharyngeal cancer originating in nasopharynx [254].

PKCι expression is elevated in HNSCCs [255]. Further, there is a positive relationship between PKCι expression and esophageal SCC cell size, lymph node metastasis, and clinical stage [256]. PKCι activation is also related to the expression of S-phase kinase-associated protein 2 through the PI3K/Akt pathway, leading to resistance of esophageal SCCs to anoikis [257]. However, downregulation of PKCι enhances the sensitivity of esophageal SCC KYSE30 cells to oxidative stress-induced apoptosis [258]. Thus, PKCι may be related to poor SCC prognosis. It also seems that high nuclear PKCθ and PKCβII expression has been correlated to a high recurrence of oral SCCs and poor survival in patients [259, 260].

3.7. Liver Cancer [Hepatocellular Carcinoma (HCC)]

Five PKC isozymes α, βII, δ, ε, and ζ are present in normal rat hepatocytes, the rat HCC cell line FAO, and in the human HCC cell line HepG2 (all but PKCδ) [261]. In Hep3B cells, different patterns of PKC isozymes have been reported, such as PKCα, δ, ε, ζ, and ι [262] and PKCα, γ, δ, ε, and ζ [263]. Furthermore, PKCβII and θ are downregulated in human HCC tissues and are correlated with the grade of HCC and hepatitis B virus infection, respectively [264]. High levels of PKCι are detected in HCC tissues compared with that in adjacent normal tissues, and show a positive correlation with cyclin E expression, pathological differentiation, and cell invasion and metastasis [265, 266]. PKCη is downregulated in HCC tissues and its downregulation is correlated with poor long-term survival in patients [267].

PKCα expression is higher in poorly differentiated HCC (e.g., SK-Hep-1) than in well-differentiated HCC (e.g., HepG2 and Hep3B) [268]. A remarkable reduction of cell growth, migration, and invasion has also been identified in the poorly differentiated HCC cell type SK-Hep-1 treated with siRNA PKCα or antisense PKCα oligonucleotide. These responses are associated with the downregulation of p38, rather than JNK and ERK signaling, indicating that p38 plays a key role in PKCα-mediated HCC cell invasion [269]. Furthermore, Tsai’s group has reported that lower levels of membrane-bound PKCα are detected in surgical specimens of HCC compared to adjacent normal tissue and they hypothesize that a negative correlation exists between PKCα activity and the size of HCC [270]. In HepG2 cells, TPA-induced generation of ROS is PKCα-dependent and leads to sustained activation of PKCα and ERK along with a reduction of E-cadherin. These changes in signaling stimulate HepG2 migration and cell cycle arrest [271–273]. TPA-induced growth arrest in the G₀/G₁ phase, upregulation of cancer suppressor gene miR-101, and downregulation of enhancer of zeste homolog 2 during embryonic ectoderm development in HepG2 cells are all PKCα-dependent [274]. Downregulation of PKCα by adding TPA into Hep3B cells also decreases the production of erythropoietin [263], which is a glycoprotein hormone that is stimulated under the hypoxic environment [275]. On the other hand, expression of PKCα and δ suppresses HGF-induced phosphorylation of ERK and paxillin, resulting in the reduction of HepG2 cell migration, whereas PKCε and ζ are required for phosphorylation of paxillin [276]. However, high levels of PKCα mRNA in HCC tissues are correlated with poor survival in patients [277].

The expression of factors associated with certain hepatic viruses can also affect the development and progression of liver carcinomas. Hepatitis B virus (HBV) envelop glycoproteins, for instance, which are collectively known as HBV surface antigens, are divided into three types, the large (LHBs), middle (MHBs), and small surface proteins (SHBs) [278]. The PreS2, which is a 55 hydrophilic amino acid chain located at the N-terminal of SHBs, is found in LHBs and MHBs [278] and stimulates the Raf1/MEK pathway through PKCα and β signaling pathways [279]. Further, LHBs can promote carcinogenesis and proliferation of HCC cells through the c-Src/PI3K/Akt pathway, which is trigged by PKCα/Raf1 activation. Stable LHB expression in HuH-7 cells also increases G₁/S cell cycle progression and antiapoptosis via c-Src activation [280].

PKCδ is involved in caspase-3-dependent apoptosis induced by the synthetic sphingosine immunosuppressant FTY720 [281]. Moreover, activation of the c-Abl/PKCδ signaling pathway results in claudin-1-induced MMP-2 expression as well as cell invasion and migration [282]. Further, PKCδ also increases phosphorylation of heat shock protein-27 (HSP-27) via p38 MAPK [283] and this may be correlated with cell migration and invasion [284].

In addition, PKCε may be involved in growth and migration of HCC cells [276, 285], while the PKCβ-specific inhibitor LY317615 or siRNA significantly reduces migration and invasion of HCC cells [286].

3.8. Lung Cancer

3.8.1. Small and Nonsmall Cell Lung Carcinoma

The two major types of lung cancer are nonsmall cell lung cancer (NSCLC) (85%) and small cell lung cancer (SCLC) (15%); NSCLC can be further divided into three subtypes: squamous-cell carcinoma, adenocarcinoma, and large-cell lung cancer [287]. NSCLCs show significantly higher survival and anticancer drug resistance than SCLCs; as they have been shown to have enhanced anticancer drug transport activity [288] and/or JNK activation [289]. Although expression of PKCα, β, ε, η, ι, and ζ is identified in NSCLCs and SCLCs, it seems that the important isozymes for therapeutic use are PKCα, β, ε, and ι.

PKCα is highly expressed in patients with NSCLCs, which higher levels being found for adenocarcinoma compared to squamous cell carcinoma [290]. PKCα exerts an important effect on antiapoptosis and metastasis of NSCLC cells. Metastasis of NSCLC cells can be stimulated by the activation of PKCα through a C-terminal class I PDZ-dependent interaction with its substrate, discs large homology-1 [291]. In addition, an increase in the activity of PKCα and nuclear PKCβ has been detected in lung metastatic nodules originating from other cancers such as HCC [292].

In regard to the antiapoptotic function of PKCα, PKCα-mediated phosphorylation of RLIP76 at Thr-297 increases doxorubicin (DOX)-transport activity, resulting in lower levels of apoptosis. This phenomenon is higher in NSCLC cells than in SCLC cells [288]. Moreover, miR-203 can regulate the expression of PKCα in NSCLC, where downregulation of PKCα by the miR-203 induces apoptosis of A549 cells while also reducing PKCα-mediated cell migration and proliferation [293]. PKCα, along with survival, is also involved in inhibition of FGF2-induced apoptosis by the stimulation of FGF2-mediated surviving expression [294]. Interestingly, a recent study has demonstrated that PKCα, through the activation of a p38 MAPK/TGF-β axis, has a suppressor function in NSCLC formation and its loss enhances K-Ras-mediated cancer initiation and progression of bronchioalveolar stem cells [295].

These data all indicate that PKCα is an important target for treatment of SCLCs and NSCLCs, but clinical trials using PKCα-specific antisense oligonucleotides show no or low efficacy in patients [296–298]. Further, clinical trials using PKCα-targeted antisense oligonucleotides aprinocarsen [296, 297] and LY900003 [298] in combination with anticancer drugs (either gemcitabine and cisplatin or gemcitabine and carboplatin) did not enhance survival and other efficacy measures in patients with advanced NSCLC.

PKCε is abnormally upregulated in human NSCLCs and is known to regulate growth and survival of NSCLC cells [299]. PKCε-depleted NSCLC cells show low growth rates in vitro and in vivo, as well as upregulation of proapoptotic genes, such as BIRC2, CASP4, CASP1, CD40, and FAS, and downregulation of prosurvival genes, such as Bcl2, BIRC3, and CD27 [300]. PKCε also enhances the proliferation of NSCLCs through the reduction of , suggesting that the serves as a negative effector in the PKCε-mediated proliferation of NSCLCs [299]. The antiapoptotic functions of PKCε in lung cancer cells involve the inhibition of TRAIL-induced cell death [301] and mitochondrial caspase signaling [302], as well as the upregulation of antiapoptotic proteins (e.g., XIAP or Bcl-XL) through S6K2, but not S6K1 signaling [303].

During metastasis of NSCLC cells, PKCε acts as a positive effector by enhancing the activation of Rac1, a Rho family member of the small GTPases, and the secretion of extracellular matrix protease (e.g., MMP-9) and protease inhibitors (e.g., tissue inhibitor of metallopeptidase 1 and 2) [304]. PKCε-dependent formation of the /tight junction protein zonula occludens-1 complex enhances migration and invasion of lung cancer cells [305].

PKCι is expressed in both SCLCs and NSCLCs and is associated with their carcinogenesis, survival and antiapoptosis [306–309]. The survival mechanisms of SCLCs and NSCLCs through PKCι involve upregulation of the antiapoptotic protein Bcl-XL [310] and S-phase kinase-associated protein 2-mediated anoikis resistance via the PI3K/Akt pathway [308]. PKCι also regulates transformed growth and invasion of NSCLC cells mainly through the Rac1/PAK/MEK/ERK signaling pathway [307, 311, 312]. After PKCι phosphorylation of epithelial cell transforming sequence 2 (Ect2) at Thr-328, binding of activated Ect2 to the PKCι-Par6 complex enhances Rac1 activity [312]. In this process, MMP-10 acts as a critical effector of the PKCι-Par6/Rac1 signaling axis that is required for anchorage-independent growth and invasion of NSCLC cells [313]. In PKCι-dependent adenocarcinoma transformation, PKCι induces four target genes, COPB2, ELF3, RFC4, and PLS1, whose expression has been correlated with PKCι activity [314]. Therefore, overexpression of PKCι is connected with poor survival in patients with NSCLC and can be used as a prognostic indicator [306].

Among oncogenic Ras genes (H-Ras, K-Ras, and N-Ras), activating mutations in K-Ras are the most frequently found in NSCLCs [315, 316] and PKCι is required for K-Ras-mediated bronchioalveolar stem cell expansion and lung cancer growth. This suggests that PKCι may be an attractive therapeutic target for the protection of lung cancer-initiating stem cells. In fact, aurothiomalate, which is a potent inhibitor of PKCι-Par6 interactions [317], can target lung cancer-initiating stem cell niches and efficiently inhibit K-Ras-mediated bronchioalveolar stem cell expansion [318]. In addition, aurothiomalate decreases the proliferation of lung cancers by inhibition of MEK/ERK signaling [311]. Interestingly, oncrasin-1, a small molecule RNA polymerase II inhibitor, requires K-Ras or PKCι for its apoptosis induction in lung cancer cells [319].

PKCη overexpression may be related to the advanced stages of NSCLC because its highest levels are identified in patients with clinical stage IV NSCLC [320]. Inhibition of PKCη enhances caspase-3 activity in NSCLC A549 cells after treatment with anticancer drugs [321]. On the other hand, EGF-mediated PKCζ activation is required in NSCLC cell chemotaxis, which plays a critical role in NSCLC cell metastasis [322].

PKCδ may be a potential therapeutic target for lung cancer because of the close relationship between its expression and antiapoptosis and cell survival. In fact, inhibition of PKCδ suppresses anchorage-independent growth, invasion, and migration in K-Ras-dependent NSCLC cells [323] and promotes chemotherapy-induced apoptosis [324]. Interaction of HSP-27 with PKCδ, especially amino acid residues 668–674 (EFQFLDI) of the V5 region, increases radioresistance and chemoresistance of NSCLC cells [325]. PS-341 (bortezomib), a proteasome inhibitor, upregulates PKCδ-dependent death receptor 5 (DR5) expression and apoptosis of NSCLC cells through the activation of ERK/RSK2 and ER stress pathways [326]. On the other hand, PKCδ also triggers the upregulation of p21 and downregulation of Rb hyperphosphorylation and cyclin A expression, resulting in PMA-induced G₁ arrest of NSCLC cell lines H441 and H358 [327].

3.8.2. Role of PKC Isozymes in Cigarette Smoke-Induced Lung Cancer

Cigarette smoke exposure, including secondhand (passive or environmental) smoke exposure, causes damage and/or apoptosis of lung cells and increases the risk of lung cancer [328]. PKC signaling has been shown to be involved in smoke-induced cell damage and apoptosis [328–330], but there is very little data specifically on the role of PKC isozymes in causing cigarette smoke-induced lung cancer. In a recent study, smoke exposure induces the phosphorylation of tumor necrosis factor-convertase (TACE; also known as ADAM17), which is a metalloprotease disintegrin. PKCε expression, activated by c-Src/ROS pathways, is required for TACE phosphorylation and EGFR activation, leading to the hyperproliferation of lung cells [329]. Further, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone (NNK) is the most potent carcinogen that is formed by nitrosation of nicotine. A recent study has suggested that NNK can induce migration and invasion of human lung cancer cells through the cooperation with c-Src/PKCι and PKCι/focal adhesion kinase (FAK) pathways [331]. PKCι can also stimulate nicotine-induced migration and invasion of human lung cancer cells through phosphorylation of μ- and m-calpains that are major members of the calpain family and can regulate cell motility [309]. Therefore, although there is not an overwhelming amount of evidence, it is likely that cigarette smoke can in fact promote invasion and migration of lung cancer cells through PKC signaling [309, 331, 332].

3.9. Melanoma

PKCα, δ, ε, ζ, and λ/ι are the PKC isozymes expressed in melanoma [333, 334]. Among them, PKCα is the most important as it is involved in differentiation, proliferation, survival, metastasis, and antiapoptosis of melanoma cells [333, 335]. Further, αv-integrin expression and αv-mediated relocalization of p53 by PKCα enhance melanoma cell survival [336]. In addition, expression of PKCα plays a critical role in the invasion and migration of melanoma cells [337, 338] as it can stimulate αvβ3-integrin-mediated invasion of melanoma cells by increasing the GTPase activity of Rac [337]. PKCα also induces melanoma vasculogenic mimicry [339] or the formation of de novo vascular networks by highly aggressive cancer cells thereby promoting the aggressive, metastatic phenotype of cancer cells [340]. However, the cellular activity of PKCα may vary, even in the same melanoma tissues (e.g., samples collected from the center of a B16 melanoma compared to those from its edge show lower PKCα activity) [341].

PKCε can participate in antiapoptosis of melanoma cells. For example, expression of PKCε attenuates the sensitization of melanoma cells to TRAIL-induced apoptosis [342], docetaxel-induced apoptosis through the activation of ERK1/2 pathway [343], and genotoxic stress-induced apoptosis by blocking the transcription factor ATF2 nuclear export and localization in the mitochondria [344].

PKCβ is detected in normal melanocytes, but is not found in isolated primary or metastatic melanoma cells [333, 334]. Introduction of PKCβII into melanoma cells suppresses HGF-induced activation of PI3K, tyrosine phosphorylation of adapter protein Gab1, and invasion activity of melanoma cells [345]. Reexpression of PKCβ in melanoma cells inhibits melanoma growth and elevates UV-induced ROS production [346]. These results indicate that PKCβ has cancer suppressive functions and its activation in melanoma can be a potential treatment option for melanoma.

Melanoma cells overexpressing PKCδ have enhanced cell metastatic capacity, likely through the release and activation of TGF-β1 [347, 348], but reduce proliferative capacity because of reduced sphingomyelinase activity [348, 349]. Furthermore, high levels of activated PKCδ enhance docetaxel-induced apoptosis via JNK activation [350].

3.10. Myeloid and Lymphocytic Leukemia

Leukemia is cancer of the blood cells and is classified as lymphocytic (lymphoid or lymphoblastic) or myeloid (myelogenous or myeloblastic) leukemia according to the type of cell that it starts in. These classifications are further broken down into four types, acute lymphocytic leukemia (ALL), CLL, AML, and chronic myeloid leukemia (CML).

3.10.1. CLL and ALL

Several PKC isozymes (PKCα, βI, βII, δ, ε, ζ, and ι) are detected in CLL, but PKCβII shows the highest expression [351–353] and plays a more important role in cell proliferation, differentiation, survival, and anticancer drug resistance. Overexpression of PKCβII in CLL is also associated with poor prognosis and patient survival [354–357]. For these reasons, PKCβII is considered a useful therapeutic target for the treatment of CLL; however, inhibition of a PKCβII activity with PKCβII-specific inhibitor (e.g., LY379196) has a minimal effect on the viability of CLL cells [351, 358]. The presence of LY379196 also failed to induce a spontaneous decrease of PKCβII mRNA and activity levels in CLL cells [358]. These data strongly suggest the existence of other critical survival signals and PKCβII activation signals in CLL cells. In fact, treatment with the PKC inhibitor RO32-0432, which can inhibit cPKCs, nPKCs, and aPKCs, markedly reduced the cell viability [351]. Further, growth factors, such as VEGF and bFGF, also appear to play an important role in maintaining PKCβII activity, because while LY379196 does not inhibit PKCβII under normal (i.e., growth factor rich) cellular condition, PKCβII is inhibited by this drug in the absence of VEGF [358].

Increased PKCβII expression also induces Akt phosphorylation, known to be a survival signal, independent of PI3K [359, 360], and controls the B cell-activating factor of the TNF family (BAFF; also known as BLyS) that is responsible for the Akt activation in response to PI3K activation [361]. During apoptosis, PKCβII downregulates proapoptotic B-cell receptor signaling in CLL cells [351]. Further, phosphorylation of antiapoptotic Bcl-2 protein at serine 70 by PKCβII increases the survival of CLL cells, but PKCβII-mediated phosphorylation of a proapoptotic BH3 only protein, BimEL, which is essential for the initial stimulation of apoptosis, leads to its proteasomal degradation [362]. A recent study has demonstrated that PKCβ-dependent activation of NF-κB in bone marrow stromal cells is also essential for the survival of CLL cells [363]. Taken together, PKCβII appears to participate in CLL cell survival by inhibiting proapoptotic signals and activating prosurvival signals.

PKCδ also plays an important role in CLL survival through the activation of PI3K [364], stabilization of Mcl-1 [365], and activation of NOTCH2 with an antiapoptotic function [366].

In ALL, PKCβ-specific inhibitors reduce cell viability in a dose-dependent manner [357]. Overexpression of PKCα has no influence on cell proliferation or cell cycle in the ALL cell line REH, but does induce anticancer drug resistance via Bcl-2 phosphorylation [367].

3.10.2. CML and AML

High levels of PKCα and PKCβII expression have been reported in myeloid leukemia and both isozymes have been shown to regulate cell differentiation, proliferation, and survival [368–370]. In CML cells, PKCβII activation is essential for cell proliferation and survival [362]. A recent study has reported that WK234, an inhibitor of PKCβ, decreases proliferation of CML K562 cells and enhances their apoptosis [371]. Furthermore, a farnesyltransferase inhibitor, BMS-214662, was determined to stimulate mitochondrial apoptosis in CD34⁺ CML cells during the early upregulation of PKCβ [372].

CML K562 cells can resist ionizing radiation through activation of the PKCδ/NF-κB pathway [373]. PKCδ is also involved in IFN-α-induced growth inhibition of CML cells through phosphorylation of Stat1 [374]. On the other hand, PKCδ may also participate in K562 cell death because of a close relationship between activation of the PKCδ/ERK pathway and high levels of Bax at hypoxia-induced apoptosis [375].

In AML cells, PKCα may play an important role in the inhibition of anticancer drug-induced apoptosis. Blocking PKCα activation enhances apoptosis in the AML cell line OCI-AML3 [370] and NB cells [376]. Furthermore, AML patients with active PKCα and PKCα-mediated Bcl-2 phosphorylation, which modulates the antiapoptotic ability of Bcl-2, have much shorter survival [377–379]. However, PKCβ may not be involved in AML cell death because PKCβ inhibitors show no effect on AML cell apoptosis [380].

Expression of PKCδ in AML cells induces cell death through the downregulation of heterogeneous nuclear ribonucleoprotein K [380], phosphorylation of eIF2α [381] and β-actin [382], and activation of MAPKs (JNK and p38) [383] and caspase-3 [384, 385]. In addition, when wogonin, a natural monoflavonoid, is added to AML U937 cells, cell differentiation and G₁ phase arrest are induced through PKCδ-mediated upregulation of p21 proteins [386]. Statin-induced AML NB4 cell differentiation [387] and ATRA-induced antileukemic responses in AML cells also require activation of PKCδ [387, 388].

3.11. Ovarian Cancer

Expression of PKCα, ι, and ζ has been found in ovarian cancer. PKCα can activate cell growth and DNA synthesis through follicle-stimulating hormone [389] and lysophosphatidic acid-induction in ovarian cancer cell invasion [390]. PKCι shows a significant correlation with cancer stage, histopathological grading, and proliferation index, but PKCα is only correlated (negatively) with histopathological grading [391]. PKCι does not directly affect ovarian cancer cell response to chemotherapy and proliferation, but it may indirectly participate in cell proliferation [392, 393].

On the other hand, PKCζ in ovarian cancer cells can act as a negative regulator of cell survival via regulation of the proapoptotic functions of protein phosphatase 2A (a survival phosphatase) and HRSL3 (a class II tumor suppressor family; also known as H-REV107-1) [394].

PKCδ is not expressed in primary and recurrent ovarian cancers [391]. However, gonadotropin-induced ovarian cancer cell proliferation requires PKCδ-mediated activation of ERK1/2 signaling [395]. Furthermore, activation of PKCδ may be associated with enhanced apoptosis in the ovarian cancer cell line COC1 [392].

3.12. Pancreatic Cancer

As mentioned above, EMT plays a critical role in promoting metastasis and invasion of cancer cells [253, 396]. Overexpression of PKCα in poorly differentiated human pancreatic cancer tissues and cell line PANC1 downregulates the activation of claudin-1 through Snail- and ERK-dependent pathways during EMT. In the well-differentiated pancreatic cancer cell line HPAC, PKCα activation reduces not only claudin-1 but also claudin-4, -7, and occludin, while Snail signaling is not changed. These signaling responses stimulated by PKCα activation lead to the downregulation of tight junction functions and enhanced antiapoptosis capabilities, which may increase cell invasion and metastasis [397, 398]. TGF-β1-mediated PKCα activation reduces the sensitivity of pancreatic cancer cells to cisplatin through overexpression of P-gp [399], stimulates cell migration, and reduces the expression of a putative tumor suppressor, phosphatase, and tensin homology [400]. In addition, PKCα has been shown to be involved in growth and differentiation of pancreatic cancer cells as the selective downregulation of PKCα enhances TNFα-induced growth arrest and differentiation in HPAC cells [401] and blocks retinoic acid-stimulated growth of the pancreatic cancer cell line AsPc1 [402]. PKCα-selective inhibition reduces carcinogenesis of pancreatic cancer and enhances the survival of tumor-bearing animals [403]. However, one study has shown that activation of PKCα can inhibit growth of the pancreatic cancer cell line DanG through the inhibition of -mediated G₁/S cell-cycle transition [404].

PKCζ participates in survival and metastasis of pancreatic cancer cells through the Stat3-dependent pathway [405–407] and Sp1-dependent VPE/VEGF expression, which is associated with cancer angiogenesis [408].

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, shows higher expression of PKCι than intraductal papillary mucinous neoplasm. Overexpression of PKCι has also been correlated with poor survival in PDAC patients [409]. High expression of PKCι in intraductal papillary mucinous neoplasm is also significantly associated with a worsening histological grade and advanced stage cancer [410]. PKCι is required for angiogenesis and metastasis of PDAC through Rac1-MEK/ERK1/2 pathway [409] and TGF-α- and K--mediated pancreatic acinar-to-ductal metaplasia [411].

PKCβ1 may play an important role in migration and antiapoptosis of pancreatic cancer cells [412]. Treatment with the PKCβ inhibitor enzastaurin reduces cancer growth, phosphorylation of GSK3β, and microvessel density in pancreatic cancer-bearing mice when combined with radiation therapy, but enzastaurin alone failed to affect cell survival, proliferation, or xenograft growth [413, 414]. On the other hand, in a study using the pancreatic endocrine cancer cell line DON1, enzastaurin (5 and 10 μM) increased caspase-mediated apoptosis, reduced phosphorylation of GSK3β and Akt, and blocked cell proliferation through the inhibition of insulin-like growth factor-1 (IGF-1) [415].

PKCδ can increase anchorage-independent growth, resistance to treatment of cytotoxic drugs, and metastasis of PANC1 [416]. Activation of the PKCδ/TG2 signaling pathway is also associated with enhanced drug resistance, metastatic phenotype, and poor patient prognosis with pancreatic cancer cells [417].

3.13. Prostate Cancer

In early prostate cancer specimens, PKCα and ζ are significantly increased, but PKCι expression shows no difference between the benign and malignant groups. Attenuation of PKCβ in early prostate cancer is associated with an increase in PKCε expression [418]. High expression of PKCδ in both low- and high grade prostate cancer has been reported [419, 420]. Furthermore, significantly high levels of PKCα, β, ε, and η have been detected in malignant prostatic carcinoma [421].

The levels of PKCα are lower in hormone-sensitive cell lines (e.g., LNCaP) compared to hormone-insensitive cell lines (e.g., PC3 or DU145) [422, 423]. PKCα activation by the arachidonic acid metabolite 12(S)-hydroxyeicosatetraenoic acid induces the motility of AT2.1 rat prostate cancer cells [424], but the reduced activation of PKCα by TGF-β1 leads to the inhibition of PC3 cell growth [425]. PKCα is also required for EGFR transactivation and ERK1/2 activation in androgen-independent human prostate cancer cells [426]. Further, these signaling responses are linked to multiple biological responses, such as proliferation, migration, and antiapoptosis, occurring in prostate cancer cells [427]. In prostate cancer progression and angiogenesis, osteopontin, a multifunctional glycosylated phosphoprotein, activates PKCα, which then plays a critical role in COX-2 expression, ultimately resulting in enhanced cell migration and invasion and angiogenesis [428].

Prostate cancer cells show PKCα-dependent proapoptotic and antiapoptotic functions. When the anticancer drug cisplatin introduced to prostate cancer cells, PCPH/ENTPD5 expression increases antiapoptosis through PKCα-mediated Bcl-2 stabilization [429]. In addition, resveratrol (3,4′,5-trihydroxystilbene), a natural stilbene with anticancer activity, induces p53-mediated apoptosis, but this apoptotic process is inhibited by PKCα activation via EGF [430].

On the other hand, PKCα activation by TPA or a methoxyflavanone derivative WJ9708012 was shown to enhance apoptosis of the prostate cancer cells through the downregulation of the serine/threonine kinase ataxia telangiectasia mutated [431], Bcl-2, and Bcl-XL in association with the degradation of the proapoptotic proteins Bid and Bad [432]. However, removal of TPA leads to the downregulation of PKCα [422]. Furthermore, LNCaP cells overexpressing PKCα had increasd sensitivity to bryostatin 1-induced apoptosis [433]. Toll-like receptors (TLRs) have important roles in host defense and tissue homeostasis during carcinogenesis through the immune system [434, 435]. The TLR3-specific ligand poly (I:C) induces apoptosis of human prostate cancer cell lines through the upregulation of JNK and p38 MAPK by PKCα activation, resulting in caspase-8-dependent apoptosis [436].

However, in a phase II clinical trial, PKCα-specific antisense oligonucleotides, ISIS 3521 and ISIS 5132, did not show clinical significant anticancer efficacy in patients with hormone-refractory prostate cancer [437].

PKCε may be the most useful therapeutic target to treat prostate cancers because it plays a key role in growth, survival, and antiapoptosis in this type of cancer. When PKCε is genetically deleted in the transgenic mouse model of prostate adenocarcinoma, proliferation, antiapoptosis, and metastasis of prostate cancer cells are dramatically reduced [438]. PKCε promotes growth and enhances survival of protein kinase D3-induced prostate cancer cells through stimulation of Akt and ERK1/2 [439], enhances cell survival of recurrent CWR-R1 prostate cancer cells through activation of the Akt survival pathway [440], and promotes growth and enhances survival of androgen-independent prostate cells through stimulation of cell proliferation-related protein synthesis (e.g., caceolin-1) and signaling (e.g., Raf1/ERK1/2) [441, 442]. In contrast, one study suggested that overexpression of PKCε does not alter the sensitivity of LNCaP cells to either PMA or androgen and the expression of caceolin-1 [423]. In addition, PKCε is required for constitutive activation of Stat3 through phosphorylation at serine 727 that is essential for prostate cancer cell invasion [438, 443].

Furthermore, PKCε-mediated antiapoptotic properties are obtained through the effects on multiple signaling pathways, such as phosphorylation and inactivation of proapoptotic Bad [444], inhibition of TNFα-induced JNK activation [444], inhibition of IκBα phosphorylation and degradation [445], and interaction of PKCε with proapoptotic Bax, all of which result in the neutralization of apoptotic signals [446]. Furthermore, PKCε increases P-gp-mediated drug resistance [447].

Several groups have also demonstrated that anticancer agents that downregulate PKCε can efficiently induce apoptosis in prostate cancer cells and inhibit their growth in vivo and in vitro. These drugs include wedelolactone, a medicinal plant-derived coumestan [448]; a second-generation selenium compound, methylseleninic acid [449]; a specific inhibitor of 5-LOX activity, MK591 [450]; and plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) [451]. One study, however, has suggested that prostate cancer cells overexpressing PKCε exhibit sensitivity to bryostatin 1-induced cell death [423].

In prostate cancer cells, PKCζ acts as a cancer suppressor through the regulation of c-Myc function [452]. Spisulosine (ES-285), which is a marine compound that has an anticancer activity, induces the death of prostate cancer cells through ceramide accumulation and PKCζ activation [453]. In a recent study, PKCζ was also shown to be involved in promoting the aggressive phenotype of LNCaP cells [454], while another study postulated that its overexpression inhibits invasive and metastatic activity in Dunning R-3327 rat prostate cancer cells [455]. Further, PKCζ activation is required for androgen-dependent cell proliferation in prostate cancer LNCaP cells and during the transition of androgen-dependent to androgen-independent prostate cancer cells [456].

In addition, downregulation of PKCη efficiently enhances TRAIL-induced apoptosis [457] and inhibition of centrosomal PKCβII expression reduces angiogenesis and prostate cancer cell growth [458].

PKCδ expression is associated with apoptosis of prostate cancer cells. The proapoptotic role of the protein tyrosine phosphatase PTPL1 in PC3 and LNCaP prostate cancer cells is PKCδ-dependent and induces inhibition of IκBα degradation and suppression of NF-κB activity [420]. Several mechanisms are involved in PKCδ-dependent apoptosis, which is triggered by PMA, anticancer drugs, or androgens; these mechanisms include upregulation of DRs (e.g., DR5) [459], activation of DR downstream effectors (e.g., caspase-8 and -3, p38, and JNK) [459–462], enhanced release of death factors (e.g., TNFα and/or TRAIL) [463, 464], upregulation of ROCK (mediated by depletion of type I transmembrane protein p23/Tmp21) [460], and ROCK-mediated upregulation of [465]. Furthermore, activation of neutral endopeptidase (NEP) and PKCδ correlates with TPA-induced apoptosis of androgen-independent prostate cancer cells. The NEP inhibits neuropeptide-induced and c-Src-mediated PKCδ degradation [466]. In anticancer drug-induced apoptosis, PKCδ and ceramide are required for cytochrome C release and caspase-9 activation in mitochondria [467].

In addition, PKCδ is overexpressed in invasive prostate cancer cell lines (e.g., DU145) and plays a critical role in migration and invasion [468]. BK-mediated migration of prostate cancer cells involves upregulation of MMP-9 and activation of the B2 receptor/PKCδ/c-Src/NF-κB signaling pathway [469]. PCPH/ENTPD5-mediated invasion of prostate cancer cells is also PKCδ-dependent [419]. Furthermore, activation of PKCδ in mice xenografted with PC3 cells can increase angiogenic activity through enhanced NADPH oxidase activity and increased levels of hypoxia-inducible factor (HIF)-1α [470].

3.14. Renal Cell Carcinoma (Kidney Cancer)

Renal cell carcinomas (RCCs) are divided into four types: clear cell (70~80%), papillary (10~20%), chromophobe (5%), and collecting duct (1%) [471, 472]. Different types of RCC show significantly different patterns in the expression of PKC isozymes. PKCβI, βII, δ, and ε are expressed in RCCs, while PKCα, βI, βII, η, and ι are found in oncocytoma, the most common benign solid renal tumor [473]. Moreover, PKCα, βI, βII, γ, δ, ε, η, θ, and λ have been detected in the human RCC cell line CCF-RC1 [474]. In human clear cell RCC cell lines clearCa-5, clearCa-19, clearCa-28, and clearCa-39 and PKCα, ε, ζ, and ι are found, while PKCβI, βII, γ, δ, η, and θ are absent [475]. Notably, lower levels of PKCα are detected in clear cell RCCs than in normal tissue [473, 476]. Furthermore, clear cell RCCs collected from patients show expression of PKCα, βI, βII, δ, ε, η, ζ, and ι, but not PKCγ and θ. A 3-fold increase in PKCη and a slight increase in PKC ζ (20%) in grades III and IV carcinomas are common in all clear cell RCCs, suggesting that these PKCs are correlated with increased cancer progression [476]. On the other hand, Pu et al. [477] have reported a significant increase of PKCζ as cancer grade increases in addition to a significant association between increased PKCζ and poor patient survival, likely because of increased resistance to the anticancer drug cisplatin. PKCζ can also activate HIF-2/HIF-α in the RCC cell line 786-O by inhibiting mRNA expression of FIH-1 [478].

PKCε is involved in growth, migration, and invasion in the clear cell RCC 769P cell line. Further, inhibition of PKCε has been shown to induce the activity of caspase-3 after adding chemotherapeutic drugs (sunitinib or 5-fluorouracil) [479]. PKCε is also associated with the regulation of β1-integrin expression [473]. PKCα and ε both play a key role in invasion of human clear cell RCC cell lines, especially the more highly invasive RCC cell lines clearCa-5 and clearCa-19 [475]. In addition, expression of netrin-1 is higher in the invasive human RCC cell line ACHN than in the weakly invasive cell line 769P, but expression of UNC5B is found to be the opposite. Stimulation of PKCα by PMA increases the expression of netrin-1 and netrin receptor UNC5B in ACHN cells, but expression of netrin-1 is much higher than that of UNC5B [480]. These results may be related with to the enhanced antiapoptosis, cell proliferation, and migration observed in these cells [481].

Expression of CUB-domain-containing protein 1 can elevate RCC migrations through PKCδ activation and correlates with poor survival of patients [482]. PKCδ activation also increases RCC migration by reducing expression and activity of β1-integrin and FAK [483]. Similar to its role in pancreatic cancer cells, IGF-1 receptor activation via PKCδ induces IGF-1-mediated invasion of RCC cells, but this invasion can be blocked by the tumor suppressor von Hippel-Lindau [484].

3.15. Thyroid Cancer

Sphingosine 1-phosphate (S1P)-mediated migration of thyroid cancer ML-1 cells is dependent on PKCα, ERK1/2, and sphingosine kinase 1 (SK1). SK1 activates S1P secretion and the activated S1P stimulates ERK1/2 phosphorylation through PKCα and βI signaling. Downregulation of PKCα reduces both VEGF-A- and S1P-induced haptotaxis, while downregulation of PKCβI only reduces S1P-induced haptotaxis [485, 486]. Furthermore, the PKCα-D294G mutant in the V3 region is found not only in thyroid cancers with more invasive phenotype [487–489], but also in pituitary adenomas [487, 489] and breast cancers [490]. This mutant reduces the transduction of extracellular signals that can suppress cancer cell growth and increase apoptosis thereby leading to a more malignant phenotype [487]. However, to date, the pituitary mutants PKCα-A294G [491] and PKCα-A881G [492] have not been identified in thyroid cancers.

Similar to the microRNA functions mentioned for other cancers (e.g., miR-31 in breast cancer or miR-203 in lung cancer), overexpression of miR-146a in the papillary thyroid cancer cell line NPA-187 decreases cell survival and induces apoptosis by suppressing PKCε expression [493]. In contrast, inhibition of PKCε in PCCL3 cells blocks p53 expression and increases the levels of murine double minute clone 2, while it has an oncogene function and antiapoptosis activity through the activation of Bcl-2 expression and reduction of Bax expression [494]. In addition, downregulation of PKCε by prolonged expression of RET/PTC increases cell survival and resistance to DOX-induced apoptosis in the thyroid cancer cell line PCCL3, while acute expression of RET/PTC activates PKCε [495]. Reduction of PKCε in papillary thyroid cancers can occur through either translational or posttranslational mechanisms [492].

Furthermore, PKCβII inhibition by enzastaurin leads to the reduction of medullary thyroid carcinoma cell proliferation and survival, indicating that PKCβII is required in these processes [496].

PKCδ activation shows an arrest in papillary thyroid cancer cell (NPA) growth at G₁ phase through the ERK//cyclin E/pRb pathway [497] as well as antiproliferative effects in the anaplastic (FRO and ARO) and follicular (ML-1) thyroid cancer cell lines through MAPK/Akt and FOXO signaling [498]. Enhanced FRO cell migration through phosphorylation of Bcl-2 associated athanogene 3 (BAG3) was also observed in some cases [498, 499].

4. PKC Isozymes as Diagnostic or Prognostic Biomarkers

PKC isozymes that are overexpressed or hyperactivated in cancer tissues can be used as immunohistochemical biomarkers during cancer diagnosis by comparing the expression in cancer tissues to that in normal tissues. For example, PKCθ has been used as a biomarker for GIST, especially GIST that is immunohistochemically negative for KIT and/or DOG1 [176–178]. Furthermore, PKCι has been used as a diagnostic biomarker for ovarian [500] and NSCLC [306], while PKCα and PKCβII have been used for breast cancer [49, 60] and diffuse large B-cell lymphoma (DLBCL; also known as non-Hodgkin’s lymphoma) [354–356], respectively.

However, in spite of usefulness of immunohistochemical biomarkers, cancer biomarkers in blood, urine, feces, or saliva have received much greater interest recently as they are easier to sample and handle; the amount of pain is reduced in patients during sampling, and the detection techniques are, overall, much less invasive compared to the analysis of tissue samples. There is currently very little data on the existence of PKC isozymes in blood, urine, feces, or saliva, but recently activated PKCα, which can act as a biomarker for cancer, was identified in blood samples collected from cancer-bearing mice as well as human patients [22, 501, 502]. Furthermore, fecal PKCβII and ζ mRNA levels significantly increase in these types of samples collected from colon cancer-bearing rats as compared with normal rats, meaning that the detection of PKCβII and ζ mRNA may apply to the diagnosis of colon cancer [503, 504].

Overexpression of PKC biomarkers is closely related to poor prognosis, poor response to chemotherapy, and poor survival. In breast cancer progression, PKCα overexpression in breast cancer exhibits poor prognosis and survival because of a decreased response to chemotherapy and the high aggressiveness of the cancer [49, 60]. Further, after endocrine therapy of breast cancer, PKCα expression (PKCα ⁺/PKCδ ⁻) correlates to estrogen receptor negativity and poor endocrine responsiveness and patient survival, but PKCδ expression (PKCα ⁻/PKCδ ⁺) increases endocrine responsiveness and patient survival [49]. A previous study has also reported that increase in PKCε correlates to positive Her2/neu receptor status, negative estrogen and progesterone receptor status, and poor survival [505]; however, this finding has recently been challenged by another study suggesting that there is no correlation between PKCε expression and clinicopathological parameters (tumor grade and estrogen/progesterone receptor negativity) and recurrence-free or 10-year survival [60]. In DLBCL, PKCβII expression is significantly associated with low response to chemotherapy and poor survival in patients [354–357]. Furthermore, PKCι can be used as a prognostic indicator in NSCLC and ovarian cancer [306, 500]. Interestingly, PKCι expression is associated with tumor stage in ovarian cancer [500], but not in NSCLS that shows an increase in PKCι expression in both early- and late-stage cancers [306].

5. PKC Isozymes and MDR

The ATP-binding cassette transporter family plays a very important role in the relationship between PKC isozymes and MDR. P-gp is a well-studied ATP-binding cassette transporter protein encoded by the MDR1 (as known as ABCB1) gene and is broadly distributed in both cancers and various normal tissues, such as kidney, adrenal, brain vessels, muscle, lung, pancreas, liver, intestine, placenta, and testis [506–508]. Since overexpression of P-gp is typical in cancer cells, P-gp-mediated MDR is one of the most serious problems facing cancer treatment. P-gp-mediated MDR is maintained by several prosurvival and antiapoptosis signals and their targets, including JNK [55], p38 [509], ERK1/2 [509], and Janus kinase [510]. Although inhibition of P-gp may increase the therapeutic effects of anticancer drugs in MDR cancer cells, P-gp inhibitors have been associated with several potential side effects [511, 512].

As mentioned in Section 3. PKC isozymes and cancer, PKC isozymes, especially PKCα and ε, are involved in the P-gp-mediated MDR in several types of cancer, such as colon cancer [119–121], pancreatic cancer [399], gastric cancer [157], breast cancer [55], leukemia [513], and prostate cancer [447]. In general, inhibition of PKC isozymes that regulate P-gp leads to reduced MDR and enhanced cancer cell apoptosis. For instance, the membrane translocation and expression levels of PKCα are significantly increased in DOX-treated human colon cancer HCT15 cells, but PKCα inhibition leads to reduced MDR and increased DOX-induced apoptosis [120]. The MDR breast cancer cell line MCF-7/ADR also exhibits higher PKCα levels and lower cell growth inhibition and apoptosis after TAM treatment, compared with untreated MCF-7 cells. However, addition of PKCα inhibitor into TAM treated MCF-7/ADR cells results in reduced MDR and enhanced apoptosis through increased JNK activity [55].

6. PKC Isozymes and Cancer Stem Cells

Cancer stem cells (CSCs) have several interesting properties, such as self-renewal, clonal formation, and chemoresistance [514, 515]. Although there is very little data regarding the role of PKC isozymes in CSC function, several studies have recently demonstrated the involvement of PKC isozymes in controlling cellular signaling in these cells.

The interaction between HA and CD44 increases PKCε-dependent phosphorylation of the stem cell marker, Nanog, in the breast cancer cell line MCF-7 [38]. Nanog activation by HA-CD44 interaction is also known to occur in ovarian cancers and HNSCCs [516–518]. The activated Nanog induces antiapoptotic and proliferative factors, such as P-gp and the inhibitor of the apoptosis protein (IAP) family (e.g., cIAP-1, cIAP-2, and XIAP), and reduces cancer suppressor proteins, such as PDCD4, resulting in enhanced antiapoptosis and anticancer drug resistance [516–518]. On the other hand, a recent study has suggested that Nanog expression is also upregulated by inhibition of PKC activity, especially PKCα and δ activity, in human cancer cell lines [519].

In glioma, combination treatment using proteasome inhibitors and TRAIL decreases the levels of PKCε mRNA and protein while also reducing PKCε-dependent activation of Akt and XIAP, resulting in cancer cell (and CSC) apoptosis. These results mean that PKCε is involved in antiapoptosis and survival of glioma stem cells [206]. Furthermore, PKCε participates in UV-radiation-induced development of SCC from precursor hair follicle stem cells [520].

As mentioned in Section 3.8. lung cancer PKCι plays a critical role in K-Ras-mediated bronchioalveolar stem cell expansion and lung cancer growth. Importantly, the small molecule PKCι inhibitor aurothiomalate can target the cancer-initiating stem cell niche and efficiently inhibit these K-Ras-mediated cellular responses [318].

Notch4 signaling activity is higher in breast cancer stem-like cells compared with differentiated cells and increases stem cell activity and cancer formation [521]. PKCα overexpression upregulates activator protein 1, which in turn mediates Notch4 activity. The activated Notch4 is closely associated with the promotion of estrogen-independent, TAM-resistant growth and chemotherapy resistance in breast cancer cells [522]. In a recent study, breast CSCs and nonbreast CSCs show differential utilization of signaling pathways during the EMT. Non-CSCs utilize c-Fos, while CSCs utilize Fra-1 to act as an effector of the EMT program. Phosphorylation of Fra-1 is performed by PKCα. High PKCα and Fra-1 expression is, therefore associated with aggressive triple-negative breast cancers, while high c-Fos expression is associated with better survival [523].

7. Summary and Overall Conclusions

In cancer, PKC isozymes play a critical role in cell proliferation, survival, invasion, migration, apoptosis, angiogenesis, and anticancer drug resistance. PKC isozymes can exhibit similar expression patterns and roles in multiple types of cancer, but in some case, they can show context specific expression and function that is dependent on the type of cancer. Among PKC isozymes, PKCα, β, ε, and δ have been the most broadly studied isozymes in relation to cancer. This may be associated with their ubiquitous expression in many tissues [524]. However, several recent studies have reported that aPKCs may also act as novel therapeutic targets for cancer treatment (e.g., PKCι in lung, ovarian, and colon cancer).

In general, overexpression of PKC isozymes is closely related to poor prognosis, poor response to chemotherapy, and poor patient survival. These results are likely caused by the high levels of cancer cell migration, invasion, survival, and anticancer drug resistance stimulated by PKC isozymes. Therefore, the overexpression of several PKC isozymes can serve as a potential cancer diagnostic marker and could be utilized as therapeutic targets.

Several PKC isozyme-specific or broad, nonspecific inhibitors have been developed and applied in phases II and III clinical trials. For example, PKCα-specific inhibitors have been used in combination with anticancer drugs in clinical trials, but satisfactory results have not yet been obtained [296–298, 437]. However, I suspect that these combination therapy trials will most likely be the only way to overcome the problem of MDR. Thus, the development of new PKC isozyme-specific inhibitors, in association with combination treatment to inhibit other non-PKC related cancer signals (e.g., c-Src signal) [45], is required.

Furthermore, there has been increasing interest in CSCs-targeted therapies as a novel treatment of cancers. Recent studies demonstrate the important role of PKC isozymes in controlling cellular signaling of CSCs. However, there is a paucity of data on the role of PKC isozymes in CSCs and further studies are required.

Abbreviations

ALL: | Acute lymphocytic leukemia
AML: | Acute myeloid leukemia
APC: | Adenomatous polyposis coli
aPKC: | Atypical PKC isozyme
ATM: | Ataxia telangiectasia mutated
ATP: | Adenosine triphosphate
bFGF: | Basic fibroblast growth factor
BK: | Bradykinin
Cdk: | Cyclin dependent kinase
CEC: | Colon epithelial cell
CLL: | Chronic lymphocytic leukemia
CML: | Chronic myeloid leukemia
Cox-2: | Cyclooxygenase type 2
cPKC: | Conventional or classic PKC isozyme
CSC: | Cancer stem cell
DAG: | Diacylglycerol
DLBCL: | Diffuse large B-cell lymphoma
DOX: | Doxorubicin
DR5: | Death receptor 5
Ect2: | Epithelial cell transforming sequence 2
EGF: | Epidermal growth factor
EGFR: | EGF receptor
ER: | Estrogen receptor
ERK: | Extracellular signal-regulated kinase
FAK: | Focal adhesion kinase
FGF: | Fibroblast growth factor
FOXO: | Forkhead box class-O
GIST: | Gastrointestinal stromal tumor
GR: | Glucocorticoid receptor
GSK3β: | Glycogen synthetase kinase 3β
HA: | Hyaluronic acid
HBV: | Hepatitis B virus
HCC: | Hepatocellular carcinoma
HGF: | Hepatocyte growth factor
HIF: | Hypoxia-inducible factor
HNSCC: | Head and neck squamous cell carcinomas
HSP: | Heat shock protein
IAP: | Inhibitor of the apoptosis protein
IFIT: | Interferon-induced protein with tetratricopeptide repeats
IGF: | Insulin-like growth factor
IP₆: | Inositol hexaphosphate
JNK: | c-Jun N-terminal kinase
MAPK: | Mitogen-activated protein kinase
MDR: | Multidrug resistant
MEK: | MAPK kinase
MMP: | Matrix metalloproteinase
mRNA: | Messenger RNA
mTOR: | Mammalian target of rapamycin
NEP: | Neutral endopeptidase
NNK: | Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl-1 butanone)
nPKC: | Novel or non-classic PKC isozyme
NSCLC: | Nonsmall cell lung cancer
PAR: | Proteinase-activated receptor
PDAC: | Pancreatic ductal adenocarcinoma
P-gp: | P-glycoprotein
PI3K: | Phosphatidylinositol 3-kinase
PKC: | protein kinase C
PLC: | Phospholipase C
PMA: | Phorbol-myristate-acetate
pRb: | Retinoblastoma protein
PS: | Phosphatidylserine
Raf1: | v-raf-1 murine leukemia viral oncogene homolog 1
Rb: | See pRb
RCC: | Renal cell carcinoma
ROS: | Reactive oxygen species
SCC: | Squamous cell carcinomas
SCLC: | Small cell lung cancer
S1P: | Sphingosine 1-phosphate
SK: | Sphingosine kinase
Stat3: | Signal transducers and activators of trancription3
TACE: | Tumor necrosis factor-convertase
TAM: | Tamoxifen
TGF: | Transforming growth factor
TLR: | Toll-like receptor
TNF: | Tumor necrosis factor
TPA: | 12-O-tetradecanolyphorbol 13-acetate
TRAIL: | TNF-related apoptosis-inducing ligand
uPA: | Urokinase-type plasminogen activator
UV: | Ultraviolet
VEGF: | Vascular endothelial growth factor
XIAP: | X-linked inhibitor of apoptosis.

Conflict of Interests

The author declares that there is no conflict of interests regarding the publication of this paper.

Acknowledgment

This work was financially supported by a Grant-in-Aid for Scientific Research (B) (KAKENHI Grant no. 23310085) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.

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