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The Role of Mitochondrial TCA Cycle Enzymes in Determining Prostate Cancer Chemosensitivity
Annual rept. 1 Mar 2010-29 Feb 2012
OREGON HEALTH AND SCIENCE UNIV PORTLAND
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Based on the results in preliminary data and in year 1 of the proposal, we hypothesize that MDH2 plays a crucial role in determining prostate cancer chemosensitivity. In year 2, we further determined the effect of inhibiting MDH2 on prostate cancer energy metabolism and response to chemotherapy. We found that MDH2 knockdown via stable shRNA significantly disrupts the metabolic efficiency and redox balance in prostate cancer cells. Further, we made a novel observation that MDH2 knockdown significantly enhances the chemotherapy induced signaling cascade that is required to exert mitochondria-based apoptosis. This provides a potential mechanism underpinning the observed clinical correlation between MDH2 and outcome of chemotherapy in prostate cancer. It also presents evidence for the first time that MDH2 can be a novel molecular target to improve prostate cancer chemotherapy.
APPROVED FOR PUBLIC RELEASE