Functional Investigation of the Mitochondrial Pyruvate Carrier in Prostate Cancer

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 DESCRIPTION (provided by applicant): Androgen receptor (AR)-induced de-novo lipid synthesis enables the growth and survival of hormone sensitive and castrate-resistant prostate cancer cells, but the metabolic alterations mediated by AR to support lipogenesis in prostate cancer are poorly understood. Lipogenesis requires pyruvate to generate lipid precursors (e.g. citrate) and recent in-vivo imaging strategies have demonstrated that, in contrast to virtually all other tumors, prostate tumors take up pyruvate more rapidly and reliably than glucose. Further, a subunit of the mitochondrial pyruvate carrier (MPC), MPC2, is a direct AR target gene, suggesting a link between AR action pyruvate trafficking, and lipogenesis. The long-term goal of this project is the identification, characterization, and targeted disruption of critical mediatorsof prostate cancer metabolism. The overall objective of the current proposal is to determine the mechanism by which AR alters pyruvate trafficking to fuel lipogenesis in prostate cancer. The overarching central hypothesis is that AR regulates the MPC to increase pyruvate flux into mitochondria to enable oncogenic growth by increasing lipogenic capacity of tumor cells. The rationale of this proposal is that characterization of the mechanism underlying increased pyruvate trafficking in prostate cancer will likely enable the development of strategies to therapeutically manipulate pyruvate flux. Such treatments could be applied to both hormone sensitive and treatment refractory castrate-resistant prostate cancer. In order to accomplish the overall objective, the central hypothesis will be tested by pursuing the following three specific aims: 1) Determine the impact of altered MPC subunit expression on pyruvate flux by experimentally modifying MPC subunit composition and measuring a variety of metabolic endpoints in addition to using mass-spectroscopy-based methods to perform 13C pyruvate tracing. 2) Define MPC-dependent tumor properties using in-vitro measurements of tumor cell proliferation, invasive capacity, and lipogenic capacity. 3) Assess the impact of MPC perturbation on prostate tumor growth in-vivo by transplanting nude mice with prostate cancer cells harboring stable modifications to MPC subunit expression or treating xenografted mice with the MPC inhibitor UK5099. Regarding outcomes, completion of the research plan will define the metabolic and oncogenic consequences of the altered MPC subunit expression pattern observed in prostate cancer. The significance of this contribution derives from the expected translational opportunities made possible by the characterization of lipogenic substrate trafficking in prostate cancer, disruption of which represents a rational therapeutic strategy in al stages of the disease. The proposed research is innovative because it focuses on understanding and disrupting tumor-specific metabolic substrate trafficking rather than enzymatic activities common to normal tissues and tumor cells alike. It is expected this expansion of focus to include substrate trafficking will broaden the approach to metabolic targeting in cancer while opening new research horizons in drug development.