In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect). Recently it became a therapeutically interesting strategy and is considered as an emerging hallmark of cancer. Hypoxia inducible factor-1 (HIF-1) is one of the key transcription factors that play major roles in tumor glycolysis and could directly trigger Warburg effect. Thus, how to inhibit HIF-1-depended Warburg effect to assist the cancer therapy is becoming a hot issue in cancer research. In fact, HIF-1 upregulates the glucose transporters (GLUT) and induces the expression of glycolytic enzymes, such as hexokinase, pyruvate kinase, and lactate dehydrogenase. So small molecules of natural origin used as GLUT, hexokinase, or pyruvate kinase isoform M2 inhibitors could represent a major challenge in the field of cancer treatment. These compounds aim to suppress tumor hypoxia induced glycolysis process to suppress the cell energy metabolism or enhance the susceptibility of tumor cells to radio- and chemotherapy. In this review, we highlight the role of natural compounds in regulating tumor glycolysis, with a main focus on the glycolysis under hypoxic tumor microenvironment.
Cells regulate glucose metabolism based on their growth and differentiation status, as well as the molecular-oxygen deficiency. The discrepancy between the rapid rate of tumor growth and the capacity of existing blood vessels to supply oxygen and nutrients makes the adaptation to hypoxia environment become the basis for the survival and growth of tumor cells. In the process of cancer metabolic reprogramming, tumor cells adapt to hypoxia through enhancing glycolysis [
Glycolysis is the metabolic process in which glucose is converted into pyruvate. In normal cells, glycolysis is prioritized only when oxygen supply is limited. When oxygen is present, pyruvate then enters the mitochondrial tricarboxylic acid (TCA) cycle to be fully oxidized to CO2 (oxidative phosphorylation). However, when the function of mitochondria was damaged or under hypoxic conditions, pyruvate is instead converted into lactate in anaerobic glycolysis [
Hypoxia inducible factor-1 (HIF-1) is a key transcription factor that plays major roles in this metabolic reprogramming (Figure
Signaling pathways and key factors involved in hypoxic induced Warburg effect. GLUT: glucose transporter; G6P: glucose-6-phosphate; HK: hexokinase; F6P: fructose-6-phosphate; PFK: phosphofructokinase; G3P: glyceraldehyde-3-phosphate; 3PG: 3-phosphoglycerate; PEP: phosphoenolpyruvate; PK: pyruvate kinase; PKM2: pyruvate kinase isoform M2; LDHA: lactate dehydrogenase; HIF: hypoxia-inducible factor; AMPK: adenosine 5′-monophosphate- (AMP-) activated protein kinase; PI3K: phosphoinositide-3-kinase; mTOR: mammalian target of rapamycin; HRE: hypoxia response element; VHL: Von Hippel-Lindau; TIGAR: TP53-induced glycolysis and apoptosis regulator.
Recently, accumulating evidence concerns natural compounds and cancer glucose metabolism. These compounds display antitumor activity to a range of human cancer cells through adapting the glucose absorption/metabolism. In comparison with synthetic compounds, natural molecules have wide range of sources, diversiform structures, multiple targets, and diversified pharmacological potential, which provide a considerable source for glycolysis inhibitors. In this review, we discuss the role of natural compounds in the regulation of aerobic glycolysis which is induced by HIF-1 and their influence on tumor growth and metastasis.
Glucose transporters and other dehydrogenates were closely related to glycolysis. Many natural compounds most likely affect expression of glucose transporters (especially GLUT1 and GLUT4) indirectly, rather controlling upstream modulatory mechanisms. Flavones, polyphenols, and alkaloids are interesting bioactive anticancer molecules isolated from plants, as several of them have been repeatedly reported to control glucose transporter activity in different cancer cell models (Table
Natural compounds interfere with glycolysis signaling pathway and function.
Compound/extract name | Chemical class | Effects on glycolysis and potential mechanisms of action | References |
---|---|---|---|
Alkannin | Naphthoquinone | Inhibits the activity of PKM2 | [ |
Apigenin | Flavones | Inhibits glucose uptake in U937 and MC3T3-G2/PA6 cells and inhibits activation of Akt and translocation of GLUT4 | [ |
Catechin | Flavanol | Inhibits glucose uptake in U937 | [ |
Cyanidin | Flavanol | Inhibits glucose uptake in U937 | [ |
Curcumin | Polyphenol | Inhibits inflammatory-induced glycolysis | [ |
Daidzein | Isoflavone | Inhibits glucose uptake in U937 | [ |
(−)-Epigallocatechin gallate | Flavanol | Inhibits insulin-stimulated glucose uptake in mouse MC3T3-G2/PA6 cells | [ |
Fisetin | Flavonol | Inhibits glucose uptake in U937 and MC3T3-G2/PA6 cells | [ |
Genistein | Isoflavone | Inhibits glucose uptake in U937 and binds on the external surface of GLUT1 | [ |
Graviola extract | Inhibits glucose uptake and strongly reduces the GLUT1, GLUT4, HKII, and LDH-A expression | [ | |
Hesperetin | Flavanone | Inhibits glucose uptake in human myelocytic U937 | [ |
Kaempferol | Flavonol | Inhibits insulin-stimulated glucose uptake in mouse MC3T3-G2/PA6 cells and inhibits activation of Akt and translocation of GLUT4 | [ |
Luteolin | Flavones | Inhibits insulin-stimulated glucose uptake in mouse MC3T3-G2/PA6 cells, inhibits insulin-stimulated phosphorylation of IR- |
[ |
4-O-Methyl alpinumisoflavone | Isoflavone | HIF-1 inhibitor; inhibits HIF-1 target genes GLUT-1 | [ |
Methyl jasmonate | Methyl ester | Detaches hexokinase from the mitochondria | [ |
Myricetin | Flavonol | Inhibits glucose uptake in human U937 cells | [ |
Naringenin | Flavanone | Inhibits glucose uptake in human U937 cells | [ |
Neoalbaconol | Sesquiterpenes | Inhibits PI3-K/Akt-HK2 pathway | [ |
Oleanolic acid | Organic acid | Induces PKM2/PKM1 switch and suppresses aerobic glycolysis | [ |
Prosapogenin A | Saponin | Inhibition of STAT3 and GLUT1, HK, and liver-type subunit of phosphofructokinase (PFKL) | [ |
Quercetin | Flavonol | Inhibits glucose uptake in U937 and MC3T3-G2/PA6 cells, inhibits activation of Akt and translocation of GLUT4, and binds on the internal side of GLUT1 | [ |
Saframycin A | Alkaloid | Forms a nuclear ternary complex with GAPDH and DNA | [ |
Shikonin | Naphthoquinone | Inhibits the activity of PKM2 | [ |
Silybin | Flavanonol | Inhibits insulin-stimulated glucose uptake in mouse MC3T3-G2/PA6 cells | [ |
|
Inhibiting cancer LDH-A activity | [ | |
Theaflavins | Flavanol | Inhibit insulin-stimulated glucose uptake in mouse MC3T3-G2/PA6 cells | [ |
The report of Vaughan et al. indicated that aerobic glycolysis can be directly induced by an inflammatory microenvironment independent of additional genetic mutations and signals from adjacent cells, and curcumin could reverse this effect [
Besides, annonaceous acetogenins, long chained fatty acid derivatives extracted from
In the present time, as a HK inhibitor, lonidamine has become new drug that interferes with mitochondrial functions, thereby inhibiting cellular oxygen consumption and energy metabolism in both normal and neoplastic cells. 2-Deoxyglucose, another HK inhibitor, was in its Phase I/II trial stage for treatment of advanced cancer and hormone refractory prostate cancer [
As an isozyme of pyruvate kinase that is specifically expressed in cancer cells, PKM2 plays an important role in the metabolism of cancer cells. The increase of tetrameric versus dimeric PKM2 isoform ratio abrogates the Warburg effect and may reactivate oxidative phosphorylation [
In recent years, LDH-A is emerging as a novel therapeutic target in inhibiting cancer aerobic glycolysis. As an important factor in nicotinamide adenine dinucleotide (NAD+) regeneration, LDH-A was overexpressed in various types of cancer including renal, breast, gastric, and nasopharyngeal cancer [
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is another key glycolytic enzyme which may play multiple noncanonical functions implicated in cell growth and survival by hypoxic-independence pathway. Saframycin A, a bacterial product of fermentation, may form a nuclear ternary complex with GAPDH and DNA and consequently exhibits antiproliferative properties in both adherent and nonadherent cancer cell models [
As the key transcription factor of glycolytic process, many tumor suppressors with emerging role in regulation of aerobic glycolysis may control glycolytic genes’ expression through HIF-1
Hypoxia can regulate erythropoietin, tyrosine hydroxylase enzyme, glucose transporter 1, glycolytic enzymes, and VEGF and a series of hypoxia induced HIF-1 gene expressions, resulting in tumor proliferation, invasion, migration, and adhesion, is constantly an important cause of malignant tumor. There is no doubt that HIF-1 is a central molecule in the control of the expression of glucose transporters and key glycolytic enzymes as well. Because HIF-1
In the past few years, many studies tried to identify natural compounds able to interfere with or inhibit the HIF-1 activity [
Similarly, other research groups have identified that the cinnamic acid derivatives baccharin and drupanin, extracted from the Brazilian green propolis, could inhibit the expression of HIF-1 and its target genes (GLUT1, HKII, and VEGF) as inhibitors of HIF-1-dependent luciferase activity [
Von Hippel-Lindau (VHL) is one of the most important tumor suppressor genes and negative regulator of hypoxic signaling pathway. Nepal et al. show that bavachinin inhibited increases in HIF-1
P53 is a tumor suppressor, induces cell-cycle arrest and cell death after DNA damage, and thus contributes to the maintenance of genomic stability. In addition to this tumor suppressor function for prooncogenic cells, P53 also negatively regulates glycolysis through activation of TIGAR (TP53-induced glycolysis regulator, an inhibitor of the fructose-2,6-bisphosphate) [
The metabolic signature of cancer cells correlates with defects in several signaling pathways. Among them, phosphoinositide-3-kinase (PI3K) and AMPK are essentially implicated.
PI3K is an important molecular signal transduction in cells. PI3K can be growth factors, cytokines, hormones, and other extracellular signals activator and also affect cellular functions, such as glucose metabolism. As mentioned above, neoalbaconol (NA) reduced the consumption of glucose and ATP generation by targeting 3-phosphoinositide-dependent protein kinase 1 (PDK1) and inhibiting its downstream PI3-K/Akt-HK2 pathway [
Wogonin could also be a good candidate for the development of new multidrug resistance (MDR) reversal agent and its reversal mechanism probably is due to the suppression of HIF-1
The AMP-activated protein kinase (AMPK) is considered as a key checkpoint to ensure energy balance in both cells and organisms. It negatively regulates aerobic glycolysis in cancer cells and suppresses tumor growth
Liu’s research found that AMPK activation is required for the antitumor activity of oleanolic acid on cancer cells. Oleanolic acid was found to activate AMPK, the master regulator of metabolism, in prostate cancer cell line PC-3 and breast cancer cell line MCF-7. Aerobic glycolysis was inhibited in cancer cells treated with oleanolic acid, in an AMPK activation-dependent manner [
Discovery of druggable mediators of cancer glucose metabolism becomes an increasingly interesting research field. In comparison with synthetic compounds, natural molecules exert multiple advantages due to their large-scale structure and diversity targets. Currently, researches have been engaged in antitumor metabolism lead compound discovery by targeting the key targets or pathways involved in the glycolysis. Firstly, compounds directly reducing the glucose uptake could be the candidate for cancer glucose metabolic inhibitor. Secondly, any compounds able to inhibit the expression or activity of glycolytic enzymes could also inhibit the tumor glycolysis. Thirdly, targeting of HIF-1
Tumor cells reprogram their glucose metabolism to rely largely on glycolysis for their energy need, even in the presence of adequate oxygen. In this view, putative modulators of cancer cell metabolism might represent a new effective class of single treatments or chemoadjuvants in cancer therapy. The emerging interplay between cancer cell metabolism and altered gene expression in cancer suggests that many of the anticancer activities ascribed to natural compounds are in fact the consequence of preventing deregulated cancer cell metabolism and growing evidence confirms this hypothesis.
Recently, accumulating evidence supports that noncoding RNAs (microRNA and LncRNA) participate in many physiological processes by modulating gene expression at the epigenetic, transcriptional, and posttranscriptional levels. At the light of this new vision, it will be important to better understand this specific area on future research and it is also essential for discovering the small molecular compounds which could affect the function or level of noncoding RNAs, such as LncRNA-UCA1 and miR143 [
Adenosine 5′-monophosphate- (AMP-) activated protein kinase
Extracellular regulated protein kinase
Glyceraldehyde-3-phosphate dehydrogenase
Glucose transporter
Hypoxia-inducible factor
Hexokinase
Hypoxia response element
Insulin-like growth factor I receptor
Insulin receptor-
Lactate dehydrogenase
Mammalian target of rapamycin
Nicotinamide adenine dinucleotide
Pyruvate dehydrogenase kinase
Liver-type subunit of phosphofructokinase
Phosphoinositide-3-kinase
Pyruvate kinase isoform M2
Reactive oxygen species
Serine/arginine-rich splicing factor 3
Signal transducer and activator of transcription 3
TP53-induced glycolysis and apoptosis regulator
Voltage-dependent anion channel
Vascular endothelial growth factor
Von Hippel-Lindau
WW domain-containing oxidoreductase.
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was supported by the funds from National Science Foundation of China (81473575 and 81102852 to Jian-Li Gao) and the young academic leader’s project of high school in Zhejiang Province (pd2013208 to Jian-Li Gao).