Modulation of RGS proteins and Ovarian Cancer Chemoresistance

描述（由申请人提供）：化疗耐药是上皮性卵巢癌的一个主要问题，必须解决这个问题才能治愈这种疾病。在卵巢癌中，LPA是一种在患者腹水中发现的生长因子，通过促进致癌生长和生存信号来促进肿瘤进展。细胞内表达的RGS蛋白负向调控LPA信号传导；因此，RGS蛋白阻断了lpa介导的卵巢癌存活信号。对多种化疗耐药模型的基因表达谱分析显示，在多种药物耐药的A2780和SKOV-3细胞中，相同的4种RGS蛋白转录物（RGS2、RGS5、RGS10和RGS17）的表达水平显著降低，这促使我们假设RGS在卵巢癌细胞中的表达缺失通过放大内源性LPA存活信号参与了化疗耐药的发生。事实上，我们的初步数据显示，在过度表达或下调RGS10和RGS17后，化疗细胞的生存能力受到显著调节。这再次表明RGS表达的缺失可能是化疗耐药发展的一个主要因素。我们进一步表明，暴露于化疗药物会导致RGS10和RGS17表达的急性下调，我们已经确定了表达改变的潜在表观遗传机制。本提案的目的是明确RGS下调在化疗耐药卵巢癌中的后果和机制。成功完成这项提议的关键结果是鉴定获得性化疗耐药的新分子介质，以及开始针对或预测卵巢癌化疗耐药的下一阶段治疗所必需的机制知识。卵巢癌中难治性疾病的防治。该项目与公共卫生相关，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蛋白如何在化疗耐药表型中钝化，从而促进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.