The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy - PubMed (original) (raw)

Figure 1

Regulation of HIF in normoxic and hypoxic conditions. Notes: HIF-α, a transcription factor, can be regulated by both hypoxic and non-hypoxic factors. In normoxia, HIF-α subunits are hydroxylated by oxygen sensors, including PHD and FIH-1 enzymes, causing polyubiquitination and proteasomal degradation of hydroxylated HIF-α subunits (red arrows). PHD and FIH-1’s activity is oxygen-dependent (red arrows); in hypoxia (blue arrows) these enzymes lose their activity due to decreased oxygenation, resulting in HIF-α protein stabilization, accumulation, and translocation into the nucleus resulting in gene transcription and biological consequences (black arrows). HIF is also modulated in a hypoxia-independent manner in response to nitric oxide (NO), reactive oxygen species (ROS), cytokines, lipopolysaccharides, and growth factors through receptor tyrosine kinases (RTK), G protein-coupled receptors (GPCRs), toll-like receptors (TLR) and alarmins receptors. The non-hypoxic HIF regulation is mediated by a number of different signaling pathways including NFκB, PI3K/AKT/mTOR, and MAPK/ERK (green arrows). These pathways, as well as ROS production, are additionally regulated by hypoxia, which results in multiple levels of HIF-α stimulation, both hypoxic and normoxic. As a result, HIF accumulation and activation alters blood vessel formation, apoptosis, metastasis, and metabolism via a number of genes including VEGF, SDF-1, Ang-2, MMPs, BNIP-3, p53, epithelial-to-mesenchymal transition (EMT), E-cad, CXCR4, LOX, CAIX, GLUT-1, and GSK (black arrows).