Hypoxia causes gene expression changes largely through the induction of the HIF1 transcription factor, and many of these changes are thought to help adapt to the adverse environment where oxygen is limiting. One class of hypoxia-induced genes that have been extensively studied is the glycolytic enzymes. These molecules are thought to be necessary to maintain energy production when reduced oxygen will not support oxidative phosphorylation within the mitochondria. While glycolysis is important to cellular growth in hypoxia, we find that the mitochondrion does not just passively stop functioning. HIF-proficient cells actively reduce oxygen consumption in hypoxia while HIF-deficient cells do not. We therefore used expression profiling and data mining during the past funding cycle to identify hypoxia-induced proteins that are targeted to the mitochondria. These putative HIF-1 regulated mitochondrial proteins do not cause apoptosis, but our functional data supports the novel concept that they actively regulate mitochondrial activity in response to hypoxia. We therefore propose to address the following four questions in this application.
In specific aim 1, we will determine if HIF-dependent gene expression changes result in altered oxygen consumption in the mitochondria through the induction of target genes BNip3/L, and/or pyruvate dehydrogenase kinase 1 (PDK1) and/or hypoxia-induced gene 1 (HIG1).
In specific aim 2 we will test the hypothesis that pharmacologic reversal of these HIF-1 dependent changes will increase oxygen consumption, diminish intracellular oxygen concentrations, and result in sensitivity to oxygen-dependent therapies such as the hypoxic cytotoxins tirapazamine (TPZ).or dinitobenzamide mustard Pr-104.
In specific aim 3 we will ask if this pharmacologic treatment that makes tumors more hypoxic also makes them more aggressive and likely to metastasize. Lastly in specific aim 4 we hypothesize that we can identify additional novel regulators of hypoxic mitochondrial function through a screen of the yeast deletion library using growth in hypoxia on non- fermentable carbon source media. The proposed experiments will allow us to determine how these molecules contribute to hypoxic regulation of mitochondrial function, what they contribute to the growth of model tumors, and what impact they have on the tumor's response to oxygen-dependent therapy.
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