Modulation of RGS proteins and Ovarian Cancer Chemoresistance

描述（由申请人提供）：化疗耐药性是上皮性卵巢癌的一个主要问题，必须加以解决，以实现治愈这种疾病。在卵巢癌中，LPA是在患者腹水中发现的生长因子，其通过促进致癌生长和存活信号传导来促进肿瘤进展。细胞中表达的RGS蛋白负调节LPA信号传导;因此，RGS蛋白钝化卵巢癌中LPA介导的存活信号。对多种化疗耐药模型的基因表达谱的分析显示，相同的四种RGS蛋白转录本，（RGS 2、RGS 5、RGS 10和RGS 17）在对多种药物具有抗性的A2780和SKOV-3细胞中以显著较低的水平表达，提示我们假设卵巢癌细胞中RGS表达的缺失通过内源性LPA存活的扩增而导致化学抗性的发展信号.事实上，我们的初步数据显示，在过表达或敲低RGS 10和RGS 17后，用化疗处理的细胞的存活率显著调节。这再次表明RGS表达的丧失可能是化学抗性发展的主要因素。我们进一步表明，暴露于化疗药物导致RGS 10和RGS 17表达的急性下调，我们已经确定了改变表达的潜在表观遗传机制。该建议的目的是确定RGS下调在化疗耐药卵巢癌中的后果和机制。成功完成该提案的关键成果是鉴定获得性化疗耐药的新型分子介质和开始下一阶段治疗靶向或预测卵巢癌化疗耐药所需的机制知识。 难治性疾病阻碍卵巢癌的治愈。该项目与公共卫生有关，因为它研究了LPA介导的癌症生存信号。它将阐明通常关闭LPA介导的生存信号的RGS蛋白如何在化学抗性表型中钝化，从而增强难治性疾病进展的机制。 公共卫生相关性：难治性疾病阻碍卵巢癌的治愈。该项目与公共卫生有关，因为它研究了LPA介导的癌症生存信号。它将阐明通常关闭LPA介导的生存信号的RGS蛋白如何在化学抗性表型中钝化，从而增强难治性疾病进展的机制。

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.