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

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, HIF1␣ 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 HIF1␣ expression has drawn interest and intense debate. Here we present an experimentally based computational model of HIF1␣ 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 HIF1␣ 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 HIF1␣ 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 HIF1␣ expression over the course of hours to days, dependent on extracellular hydrogen peroxide levels and largely independent of initial intracellular levels, during hypoxia.The transcription factor hypoxia-inducible factor (HIF) plays a critical role in the mammalian response to oxygen (O 2 ) levels. HIF1, the first characterized member of the HIF family, transcriptionally activates hundreds of genes associated with angiogenesis in cancer, exercise, and ischemia, as well as energy metabolism, nutrient transport, cell cycle, and cell migration (85, 98).HIF1␣ and HIF1␤ make up the HIF1 heterodimer. The ␤-subunit is constitutively expressed in cells. Expression of the ␣-subunit may be induced by a number of pathways, and its degradation is highly sensitive to O 2 levels. Called a master switch for hypoxic gene expression (76, 85), intracellular HIF1␣ in normoxia is experimentally undetectable; during hypoxia, it rapidly accumulates in the cell nucleus and triggers gene expression. Molecular players involved in this process have come to light over the past 6 years; research has begun to define roles for prolyl hydroxylases, iron, ascorbate, hydrogen peroxide, 2-oxoglutarate, succinate, and von Hippel-Lindau protein in the HIF1 pathway.Concomitantly, the study of reactive oxygen species (ROS) and the interest in antioxidants as potential dietary supplements for prevention of cancer, cardiac dysfunction, and neurodegeneration has grown rapidly. Ongoing debate surrounds the role of these co...

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