HIF-1: upstream and downstream of cancer metabolism

Abstract

Hypoxia-inducible factor 1 (HIF-1) plays a key role in the reprogramming of cancer metabolism by activating transcription of genes encoding glucose transporters and glycolytic enzymes, which take up glucose and convert it to lactate; pyruvate dehydrogenase kinase 1, which shunts pyruvate away from the mitochondria; and BNIP3, which triggers selective mitochondrial autophagy. The shift from oxidative to glycolytic metabolism allows maintenance of redox homeostasis and cell survival under conditions of prolonged hypoxia. Many metabolic abnormalities in cancer cells increase HIF-1 activity. As a result, a feed-forward mechanism can be activated that drives HIF-1 activation and may promote tumor progression.

Figure 1

HIF-1 and metabolism. (A) Regulation of HIF-1α protein synthesis and stability and HIF-1-dependent metabolic reprogramming. The rate of translation of HIF-1α mRNA into protein in cancer cells is dependent upon the activity of the mammalian target of rapamycin (mTOR), which is determined by the activity of upstream tumor suppressor proteins (green ovals) and oncoproteins (orange rectangles). Arrows indicate stimulation, blocked lines indicate inhibition. HIF-1α protein stability is regulated by O₂- and α-ketoglutarate-dependent prolyl hydroxylation catalyzed by PHD2. Hydroxylation is required for the binding of the von Hippel-Lindau protein (VHL), which recruits a ubiquitin ligase that targets HIF-1α for proteasomal degradation. Loss of function for any of the tumor suppressor genes encoding fumarate hydratase (FH), isocitrate dehydrogenase (IDH), or succinate dehydrogenase (SDH) inhibits PHD2 activity. HIF-1α dimerizes with HIF-1β (not shown) and activates transcription of target genes encoding proteins (yellow rectangles) that play key roles in the metabolic reprogramming of cancer cells. Abbreviations: PTKs, protein tyrosine kinases; PI3K, phosphatidylinositol-3-kinase; S6K, ribosomal protein S6 kinase; ALD, aldolase; PGK, phosphoglycerate kinase; ENO, enolase; PKM, pyruvate kinase M. Other HIF-1-regulated glycolytic enzymes that are not shown: glucosephosphate isomerase, phosphofructokinase L, triosephosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, and phosphoglyceromutase. (B) Oxidative and glycolytic metabolism of glucose. HIF-1-regulated genes (yellow ovals) play key roles in converting extracellular glucose to extracellular lactate and blocking entry of pyruvate into the tricarboxylic acid cycle. Loss of function for each of the enzymes shown in green is associated with tumor formation and HIF-1α stabilization due to PHD2 inhibition by accumulation of the enzyme substrate. Arrows indicate the direction of the cycle. CS, citrate synthase; αKGDH, α-ketoglutarate dehydrogenase; SCS, succinyl-CoA synthetase; MDH, malate dehydrogenase.