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，必须加以解决才能治愈这种疾病。在卵巢癌中，LPA是一种在患者腹水中发现的生长因子，通过促进肿瘤生长和生存信号来促进肿瘤进展。在细胞中表达的RGS蛋白负向调节LPA信号；因此，RGS蛋白在卵巢癌中钝化LPA介导的生存信号。对多种化疗耐药模型的基因表达谱分析表明，相同的四种RGS蛋白转录本(RGS2、RGS5、RGS10和RGS17)在对多种药物耐药的A2780和SKOV-3细胞中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生存信号而促进化疗耐药的发展。事实上，我们的初步数据显示，在过表达或敲除RGS10和RGS17之后，接受化疗的细胞的生存能力得到了显著的调节。这再次表明RGS表达的缺失可能是化疗耐药发生的一个主要因素。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，我们已经确定了这种表达变化的潜在表观遗传学机制。这项建议的目的是明确RGS下调在化疗耐药卵巢癌中的后果和机制。成功完成这一提议的关键结果是识别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。难治性疾病阻碍了卵巢癌的治愈。该项目与公共健康相关，因为它研究了LPA在癌症中介导的生存信号。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被钝化，从而促进难治性疾病的进展。 公共卫生相关性：难治性疾病阻碍了卵巢癌的治愈。该项目与公共健康相关，因为它研究了LPA在癌症中介导的生存信号。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被钝化，从而促进难治性疾病的进展。

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.