Novel Role of Hypoxia in Ovarian Cancer Chemo Resistance through Epigenetic
Noelle Cutter, Tyler Walther, Liam Gallagher, Michael O’Sullivan, Benjamin Honigsfeld, Kim Doyle, Nevenka Dimitrova, Robert Lucito

Abstract
Ovarian cancer is the fifth deadliest cancer in woman, and epithelial malignancies account for 90% of cases. Tumor recurrence after chemotherapy or radiation remains a major obstacle to successful ovarian cancer treatment. Despite the large number of studies, molecular events that govern the emergence of aggressive therapy-resistant cells after chemotherapy are poorly defined. Genetic modifications, such as copy number variation (CNV), play an important role in controlling the expression of genes that are involved in chemo resistance. We analyzed CNV data that is publically available through the Cancer Genome Atlas and others. Of particular interest was the transcription factor HIF1α which plays an integral role in oxidative stress response such as those induced by chemotherapy reagents? The present study provides evidence for the rare escape of tumor cells from drug-induced cell death by entering a non-cycling senescent state. We report the adaptive response of human ovarian surface epithelium cells to CoCl2, a chemical hypoxia-mimicking agent resulting in a senescent-like state of chemo resistant cells. The effect of the treatment was evaluated on CNV of HIF-1α gene expression, cell proliferation, survival, and tumor invasiveness. We show here that CNV duplication events of HIF1α results in an oxidative stress response in cells leading to chemo resistance through the induction of cellular senescence. Understanding the molecular events associated with chemo resistance will ultimately lead to better patient treatment and outcomes.

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