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

Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, 613 Traylor Bldg, 720 Rutland Ave., Baltimore, MD 21205, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 07/2008; 28(16):5106-19. DOI: 10.1128/MCB.00060-08
Source: PubMed


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, HIF1alpha 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 HIF1alpha expression has drawn interest and intense debate. Here we present an experimentally based computational model of HIF1alpha 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 HIF1alpha 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 HIF1alpha 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 HIF1alpha expression over the course of hours to days, dependent on extracellular hydrogen peroxide levels and largely independent of initial intracellular levels, during hypoxia.

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    • "Thiol groups are one of the members of the antioxidant system as they have been revealed to devastate the reactive oxygen species (ROS) and other free radicals by enzymic and nonenzymic mechanisms [13] [14]. It has been recently advocated that genetic factors may also have an effect on the ROS system activity and ROS production [15]. It has been found that the exposure of proteins to oxidative stress resulted in decrease and functional defects in the thiol groups [16] [17]. "
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    • "Kinetic parameters of these antioxidant enzymes in the model were based on available experimental data on Tpx, Trx, and TR enzymes (see Table S2 in Supplement I). The concentrations of the phenomenological enzymes (Pr, PSH, and Red) were determined as a result of the fitting of experimental data on the basal level of intracellular H 2 O 2 concentration (Qutub and Popel, 2008). In the model we neglected the processes of H 2 O 2 degradation through the oxidation of cellular proteins and the generation of free radicals by H 2 O 2 . "
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    • "However, Fig. 4 shows that the total intracellular concentration of iron remains unaffected in the presence of extracellular Asc, implying that the cytoprotective effects of iron against Asc-provoked cell death are not related to iron deficiency. Further, it is known that the level of hypoxia inducible factor-1 (HIF-1), a transcription factor that is involved in the regulation of different aspects of cancer cell biology, can be affected by Asc303132, iron3334, and H2O235. Fig. 5 shows characteristic micrographs, intensities and histograms of HIF-1α immunofluorescence. "
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