HIF-1α stabilization requires mitochondrial respiration
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Abstract
Hypoxia inducible factors (HIFs) are oxygen sensitive transcription factors that allow adaptation to hypoxic environments by altering their metabolic programming and gene expression. HIF-1 consists of an oxygen-regulated subunit HIF-1α and a constituvely expressed subunit HIF-1β. Overexpression of HIF-1 has been found in range of human cancer cell types, and targeting HIF-1 could represent a novel approach in treating cancer. The goal of this project was to determine if mitochondrial respiratory integrity is required for HIF-1α stabilization. This was done by induction of mitochondrial respiratory defect through tetracycline-controlled expression of a dominant negative form of DNA polymerase γ followed by hypoxic exposures. NAC was added to Tet/on cultures to investigate the contribution of ROS production to HIF-1α stabilization. Tet/off and HTC116 p53-/- cell lines were used to further investigate if the requirement of mitochondrial respiration integrity is important for HIF-1 stabilization. HIF-1α expression was not observed in either of the cell lines with long term mitochondrial respiratory defect and addition of NAC did not have a significant different effect. Early inhibition of the mitochondrial respiratory complexes leads to a degradation of HIF-1α confirming that mitochondrial respiratory function is required for HIF-1α stabilization in hypoxic condition.
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This presentation is supported by the National Cancer Institute through the U54 CA096297/CA096300: UPR/MDACC Partnership for Excellence in Cancer Research Training Program.