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.
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.
|Altman, Molly K; Alshamrani, Ali A; Jia, Wei et al. (2015) Suppression of the GTPase-activating protein RGS10 increases Rheb-GTP and mTOR signaling in ovarian cancer cells. Cancer Lett 369:175-83|
|Hooks, Shelley B; Murph, Mandi M (2015) Cellular deficiency in the RGS10 protein facilitates chemoresistant ovarian cancer. Future Med Chem 7:1483-9|
|Cacan, Ercan; Ali, Mourad W; Boyd, Nathaniel H et al. (2014) Inhibition of HDAC1 and DNMT1 modulate RGS10 expression and decrease ovarian cancer chemoresistance. PLoS One 9:e87455|
|Ali, Mourad W; Cacan, Ercan; Liu, Yuying et al. (2013) Transcriptional suppression, DNA methylation, and histone deacetylation of the regulator of G-protein signaling 10 (RGS10) gene in ovarian cancer cells. PLoS One 8:e60185|
|Altman, Molly K; Nguyen, Duy T; Patel, Santosh B et al. (2012) Regulator of G-Protein Signaling 5 Reduces HeyA8 Ovarian Cancer Cell Proliferation and Extends Survival in a Murine Tumor Model. Biochem Res Int 2012:518437|
|Nguyen, Giang Huong; Murph, Mandi M; Chang, Joe Y (2011) Cancer stem cell radioresistance and enrichment: where frontline radiation therapy may fail in lung and esophageal cancers. Cancers (Basel) 3:1232-52|
|Breuer, Eun-Kyoung Yim; Murph, Mandi M (2011) The Role of Proteomics in the Diagnosis and Treatment of Women's Cancers: Current Trends in Technology and Future Opportunities. Int J Proteomics 2011:|
|Hooks, Shelley B; Callihan, Phillip; Altman, Molly K et al. (2010) Regulators of G-Protein signaling RGS10 and RGS17 regulate chemoresistance in ovarian cancer cells. Mol Cancer 9:289|