Abstract
BackgroundA critical therapeutic challenge in epithelial ovarian carcinoma is the development of chemoresistance among tumor cells following exposure to first line chemotherapeutics. The molecular and genetic changes that drive the development of chemoresistance are unknown, and this lack of mechanistic insight is a major obstacle in preventing and predicting the occurrence of refractory disease. We have recently shown that Regulators of G-protein Signaling (RGS) proteins negatively regulate signaling by lysophosphatidic acid (LPA), a growth factor elevated in malignant ascites fluid that triggers oncogenic growth and survival signaling in ovarian cancer cells. The goal of this study was to determine the role of RGS protein expression in ovarian cancer chemoresistance.ResultsIn this study, we find that RGS2, RGS5, RGS10 and RGS17 transcripts are expressed at significantly lower levels in cells resistant to chemotherapy compared with parental, chemo-sensitive cells in gene expression datasets of multiple models of chemoresistance. Further, exposure of SKOV-3 cells to cytotoxic chemotherapy causes acute, persistent downregulation of RGS10 and RGS17 transcript expression. Direct inhibition of RGS10 or RGS17 expression using siRNA knock-down significantly reduces chemotherapy-induced cell toxicity. The effects of cisplatin, vincristine, and docetaxel are inhibited following RGS10 and RGS17 knock-down in cell viability assays and phosphatidyl serine externalization assays in SKOV-3 cells and MDR-HeyA8 cells. We further show that AKT activation is higher following RGS10 knock-down and RGS 10 and RGS17 overexpression blocked LPA mediated activation of AKT, suggesting that RGS proteins may blunt AKT survival pathways.ConclusionsTaken together, our data suggest that chemotherapy exposure triggers loss of RGS10 and RGS17 expression in ovarian cancer cells, and that loss of expression contributes to the development of chemoresistance, possibly through amplification of endogenous AKT signals. Our results establish RGS10 and RGS17 as novel regulators of cell survival and chemoresistance in ovarian cancer cells and suggest that their reduced expression may be diagnostic of chemoresistance.
Highlights
A critical therapeutic challenge in epithelial ovarian carcinoma is the development of chemoresistance among tumor cells following exposure to first line chemotherapeutics
We have recently shown that Regulators of G-protein Signaling (RGS) proteins suppress lysophosphatidic acid (LPA) stimulated growth signals in ovarian cancer cells [8,11], and identified over a dozen RGS transcripts expressed in ovarian cancer cells, many of which are differentially expressed in normal ovarian cells versus ovarian cancer cell lines [12]
We further demonstrate that RGS10 and RGS17 expression regulates the cellular toxicity of multiple cytotoxic chemotherapeutics, which enhances the viability of these tumor cells in the presence of chemotherapy
Summary
A critical therapeutic challenge in epithelial ovarian carcinoma is the development of chemoresistance among tumor cells following exposure to first line chemotherapeutics. Ovarian cancer is a solid malignancy often initially responsive to cytotoxic chemotherapy, but the high 5year mortality rate (>55%) is a result in part of the tumor cells’ ability to develop resistance to chemotherapy This “chemoresistance” is the specific acquired resistance against the action of therapeutic agents (i.e. cytotoxic chemotherapy) that makes further treatment refractory. Its occurrence in patients with ovarian cancer is common because this disease has characteristically dormant cells within the peritoneal cavity that proliferate slowly, allowing for the development or selection of resistance to aggressive treatment. It is this pool of persistent, dormant, chemoresistant cells that prevents the clinical and pharmacological ability to cure ovarian cancer [1]. G-proteins are the critical mediators of LPA signaling cascades, and proteins that regulate G-protein activity control the strength of LPA stimulated responses in ovarian cancer cells
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