Ascorbate and H₂O₂ differentially control intracellular oxygen sensitivity via hypoxia-inducible factor HIF1α in cancer and ischemia Free

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Regulation of transcription factor hypoxia-inducible factor 1 (HIF1) has been linked to inflammation, poor prognosis in many cancers, and severity of neurodegeneration after ischemic stress. In hypoxia, the HIF1α protein accumulates intracellularly and leads to the activation of several hundred genes involved in cell proliferation, metabolism and angiogenesis. Considering its activity, the HIF1 pathway looks increasingly attractive as a target of therapeutic studies. Independently, antioxidants have shown promise in lowering the risk of some cancers. The mechanism of how antioxidants and reactive oxygen species influence HIF1 expression has drawn intense debate. Studies show both increased and decreased HIF1α expression in response to reactive oxygen species. Here we present an experimentally-based computational model of HIF1α protein degradation that proposes mechanisms for how pro- and antioxidants affect the HIF1 pathway. The model predicts how the same compounds could alter HIF1 differently in cancerous versus ischemic microenvironments.

The model consists of kinetic equations mapping the molecular steps in HIF1α degradation in normoxia, HIF1α synthesis in chronic hypoxia, and effects of the enzyme and cofactors involved in the HIF hydroxylation pathway. We use the model to demonstrate changes in HIF1α expression caused by ascorbate, iron and the reactive oxygen species H₂O₂, compounds involved in HIF1α hydroxylation. The model is applied to two representative hypoxic microenviromental conditions: anaerobic cancer cells and endothelial cells during ischemia. Results predict distinctly different levels of HIF1α in the two microenviroments even while at the same oxygen tension, based on the relative effects of pro- and antioxidants. Finally, we propose ways to alter the efficacy of ascorbate supplementation by dehydroascorbic acid tranport via the GLUT1 transporter, expressed differentially in tumors compared to normal or ischemic tissue. The model demonstrates potential molecular mechanisms for use in cancer prevention, as well as repression of angiogenesis and inflammatory signaling regulated by HIF1α expression.