Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy

Abstract

Hypoxia-inducible factors (HIFs) mediate adaptive physiological responses to hypoxia. In human cancers that are accessible for O(2) electrode measurements, intratumoral hypoxia is common and severe hypoxia is associated with increased risk of mortality. HIF activity in regions of intratumoral hypoxia mediates angiogenesis, epithelial-mesenchymal transition, stem-cell maintenance, invasion, metastasis, and resistance to radiation therapy and chemotherapy. A growing number of drugs have been identified that inhibit HIF activity by a variety of molecular mechanisms. Because many of these drugs are already FDA-approved for other indications, clinical trials can (and should) be initiated to test the hypothesis that incorporation of HIF inhibitors into current standard-of-care therapy will increase the survival of cancer patients.

Figure 1

Regulation of HIF-1 activity by oncoproteins and tumor suppressors. HIF-1 activity is stimulated by oncoprotein (red) gain-of-function. HIF-1 activity is inhibited by tumor suppressors (green) and their loss-of-function therefore stimulates HIF-1 activity.

Figure 2

HIF target genes encode proteins involved in critical aspects of cancer progression. The list of HIF-regulated genes (shown in red) is intended to be illustrative rather than comprehensive. (A) HIF target genes (locus abbreviations in parentheses) that promote cell immortalization, stem cell self-renewal, and autocrine growth and survival include those encoding adrenomedullin (ADM), endothelin 1 (EDN1), erythropoietin (EPO), glucose-6-phosphate isomerase (GPI), insulin-like growth factor 2 (IGF2), octamer binding protein 4 (OCT4), phosphoglycerate mutase (PGM), telomerase (TERT), transforming growth factor α (TGFA), and vascular endothelial growth factor (VEGF). (B) HIF-1 target genes involved in metabolic reprogramming include glucose transporter 1 and 3 (GLUT1, GLUT3), hexokinase 1 and 2 (HK1, HK2), glycolytic enzymes aldolase A (ALDOA), enolase 1 (ENO1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphofructokinase L (PFKL), phosphoglycerate kinase 1 (PGK1), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA). The enzymatic activity of pyruvate dehydrogenase (PDH) is inhibited by PDH kinase 1 (PDK1), thereby blocking the conversion of pyruvate to acetyl coenzyme A (AcCoA) for entry into the tricarboxylic acid (TCA) cycle. Two members of the BCL2 family of mitochondrial proteins (BNIP3, BNIP3L) trigger mitochondrial selective autophagy. Lactate and hydrogen ion (H⁺) generated by glycolysis are effluxed from the cell through the activity of the monocarboxylate transporter 4 (MCT4), sodium-hydrogen exchanger 1 (NHE1), and carbonic anhydrase 9 (CAR9). HIF-1 may also regulate the expression of the transketolase (TKT) and TKT-like 2 (TKTL2) enzymes of the non oxidative arm of the pentose phosphate pathway (PPP). (C) HIFs stimulate tumor vascularization by activating transcription of the genes encoding VEGF, stromal-derived factor 1 (SDF1), placental growth factor (PGF), platelet-derived growth factor B (PDGFB), and angiopoietin 1 and 2 (ANGPT1, ANGPT2). (D) HIF target genes that promote epithelial mesenchymal transition include inhibitor of differentiation 2 (ID2), snail 1 and 2 (SNAI1, SNAI2), transcription factor 3 (TCF3), TGFA, vimentin (VIM), and zinc finger E-box-binding homeobox 1 and 2 (ZEB1, ZEB2). (E) HIF target genes promoting invasion and metastasis include those encoding autocrine motility factor (AMF; also known as GPI), angiopoietin- like 4 (ANGPTL4), cathepsin C (CTSC), lysyl oxidase (LOX), LOX-like 2 and 4 (LOXL2, LOXL4), L1 cell adhesion molecule (L1CAM), Met proto-oncogene/hepatocyte growth factor receptor (MET), matrix metalloproteinase 2, 9, and 14 (MMP2, MMP9, MMP14), and the urokinase plasminogen activator receptor (PLAUR).

Figure 3

Molecular mechanism of action of drugs that inhibit HIF-1. The steps required for the transactivation of target genes by HIF-1 are shown in the colored ovals and the drugs that inhibit each step are shown below. Abbreviations: AF, aminoflavone, MSC, Se-methylselenocysteine.