Modulation of RGS proteins and Ovarian Cancer Chemoresistance

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DESCRIPTION (provided by applicant): Chemoresistance is a major problem in epithelial ovarian carcinoma that must be addressed to achieve a cure for this disease. In ovarian cancer, LPA is a growth factor found in patient ascites fluid that enhances tumor progression by promoting oncogenic growth and survival signaling. RGS proteins expressed in cells negatively regulate LPA signaling; thus, RGS proteins blunt LPA-mediated survival signals in ovarian cancer. Analysis of gene expression profiles in multiple models of chemoresistance revealed that the same four RGS protein transcripts (RGS2, RGS5, RGS10 and RGS17) are expressed at significantly lower levels in A2780 and SKOV-3 cells resistant to multiple drugs, prompting us to hypothesize that loss of RGS expression in ovarian cancer cells contributes to the development of chemoresistance through amplification of endogenous LPA survival signals. Indeed, our preliminary data shows a significant modulation in viability of cells treated with chemotherapy after overexpressing or knocking-down RGS10 and RGS17. This again suggests that the loss of RGS expression could be a major factor in the development of chemoresistance. We have further shown that exposure to chemotherapeutic drugs causes acute downregulation of RGS10 and RGS17 expression, and we have identified potential epigenetic mechanism for the altered expression. The objective of this proposal is to define the consequence and mechanism of RGS downregulation in chemoresistant ovarian cancer. The key outcomes of the successful completion of this proposal are the identification of novel molecular mediators of acquired chemoresistance and the mechanistic knowledge necessary to begin the next phase of therapeutics targeting or predicting chemoresistance in ovarian cancer. Refractory disease prevents cure in ovarian cancer. The project is relevant to public health because it investigates LPA-mediated survival signaling in cancer. It will elucidate the mechanism of how RGS proteins that normally turn off LPA-mediated survival signaling are blunted in chemoresistant phenotypes, enhancing refractory disease progression. PUBLIC HEALTH RELEVANCE: Refractory disease prevents cure in ovarian cancer. The project is relevant to public health because it investigates LPA-mediated survival signaling in cancer. It will elucidate the mechanism of how RGS proteins that normally turn off LPA-mediated survival signaling are blunted in chemoresistant phenotypes, enhancing refractory disease progression.