Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways

Abstract

Both tumor hypoxia and dysregulated metabolism are classical features of cancer. Recent analyses have revealed complex interconnections between oncogenic activation, hypoxia signaling systems and metabolic pathways that are dysregulated in cancer. These studies have demonstrated that rather than responding simply to error signals arising from energy depletion or tumor hypoxia, metabolic and hypoxia signaling pathways are also directly connected to oncogenic signaling mechanisms at many points. This review will summarize current understanding of the role of hypoxia inducible factor (HIF) in these networks. It will also discuss the role of these interconnected pathways in generating the cancer phenotype; in particular, the implications of switching massive pathways that are physiologically 'hard-wired' to oncogenic mechanisms driving cancer.

Figure 1

Regulation of HIF-1 by oxygen dependent prolyl and asparaginyl hydroxylation of HIF-1α. Hypoxia inducible factor (HIF)-1α, a basic-Helix-Loop-Helix Per-AHR/ARNT/Sim (bHLH-PAS) domain containing protein, contains three residues that are targets for regulatory hydroxylation. P402 and P564 are targeted by the prolyl hydroxylase domain (PHD) enzymes (note that PHD3 can only hydroxylate P564) and N803 by factor inhibiting HIF (FIH). P402 is located in the N-terminal, and P564 in the C-terminal, O₂-dependent degradation domain. Prolyl hydroxylated HIF-1α is recognized by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex, leading to degradation in normoxia. Interestingly, prolyl and asparaginyl hydroxylation are differentially sensitive to hypoxia. Inhibition of prolyl hydroxylation alone (lower right) is sufficient to allow HIF-1α to escape from pVHL E3-dependent proteolytic destruction and form an active transcriptional complex with HIF-β through activity of the N-terminal activation domain (NAD). In more severe hypoxia, HIF-1α asparaginyl hydroxylation is also inhibited (lower left) allowing recruitment of p300/CBP co-activators to its C-terminal transactivation domain (CAD), and enhancing the transcription of a specific set of HIF-1 target genes. (HRE, hypoxia-response element).

Figure 2

Oncogenic signals act through multiple parallel pathways to activate HIF and its target genes. In addition to regulation by hypoxia, hydroxylation of hypoxia inducible factor (HIF)-α may be influenced by metabolic and redox signals. In cancer, all of these micro-environmental stresses can inhibit hydroxylation leading to accumulation of HIF. Oncogenic signals also impinge on the HIF pathway at many other points, including transcription, translation, post-translational modification and pVHL-mediated degradation of HIF-α polypeptides. In addition, oncogenic signals activate many HIF target genes directly.

Figure 3

Schematic illustrating the action of HIF on multiple aspects of cellular metabolism.

Figure 4

Schematic illustrating 'hard-wired’ interconnections among growth promoting signals, HIF and metabolic/angiogenic pathways. During physiological growth these pathways are tightly regulated (left panel). In oncogenesis, increased growth activates the 'hard-wired’ connections to generate the metabolic and angiogenic characteristics of cancer (upper right panel). Because different oncogenic signals have quantitatively and qualitatively different connections with hypoxia inducible factor (HIF) and metabolic/angiogenic pathways, dysregulated stochastic activation of oncogenic signaling by somatic mutation in cancer has the potential to 'co-select’ grossly disorganized metabolic and angiogenic phenotypes (lower right panel).