Reactive Oxygen Species Regulate Hypoxia-Inducible Factor 1α Differentially in Cancer and Ischemia

Abstract

ABSTRACT In exercise, as well as cancer and ischemia, hypoxia-inducible factor 1 (HIF1) transcriptionally activates hundreds of genes vital for cell homeostasis and angiogenesis. While potentially beneficial in ischemia, upregulation of the HIF1 transcription factor has been linked to inflammation, poor prognosis in many cancers, and decreased susceptibility of tumors to radiotherapy and chemotherapy. Considering HIF1's function, HIF1α protein and its hydroxylation cofactors look increasingly attractive as therapeutic targets. Independently, antioxidants have shown promise in lowering the risk of some cancers and improving neurological and cardiac function following ischemia. The mechanism of how different antioxidants and reactive oxygen species influence HIF1α expression has drawn interest and intense debate. Here we present an experimentally based computational model of HIF1α protein degradation that represents how reactive oxygen species and antioxidants likely affect the HIF1 pathway differentially in cancer and ischemia. We use the model to demonstrate effects on HIF1α expression from combined doses of five potential therapeutically targeted compounds (iron, ascorbate, hydrogen peroxide, 2-oxoglutarate, and succinate) influenced by cellular oxidation-reduction and involved in HIF1α hydroxylation. Results justify the hypothesis that reactive oxygen species work by two opposite ways on the HIF1 system. We also show how tumor cells and cells under ischemic conditions would differentially respond to reactive oxygen species via changes to HIF1α expression over the course of hours to days, dependent on extracellular hydrogen peroxide levels and largely independent of initial intracellular levels, during hypoxia.