Abstract 707: Acquisition of chemoresistance and epithelial to mesenchymal phenotype is linked with activation of the endothelin A receptor pathway in ovarian carcinoma cells

Abstract

Abstract Understanding the molecular mechanisms underlying chemoresistance is of utmost importance for improving the treatment of epithelial ovarian cancer (EOC). Emerging evidence suggests molecular and phenotypic association between chemoresistance and epithelial-mesenchymal transition (EMT) in cancer cells. Endothelin-1 (ET-1) and the endothelin A receptor (ETAR) axis is implicated in the pathobiology of EOC by driving different tumor-promoting effects, including EMT. By employing two cisplatin- and taxol-resistant ovarian cancer cell lines, we demonstrated that in the resistant EOC cells ET-1 and ETAR are upregulated, at both mRNA and protein level, paralleled by enhanced MAPK and AKT phosphorylation and cell proliferation. To assess whether the chemoresistance in A2780 cells was associated with EMT molecular changes, we examined the expression of epithelial and mesenchymal markers. Enhanced Snail, Slug, Twist, N-cadherin and vimentin mRNA expression was observed in resistant cells, associated with a concomitant decrease in E-cadherin expression and promoter activity. Moreover, ET-1 induced a significant induction of Snail promoter activity in resistant cells, and the E-cadherin promoter sequences were detected bound to Snail in a time-dependent manner, as demonstrated by chromatin immunoprecipitation assays, suggesting that the ET-1-dependent and sustained binding of Snail in the E-cadherin promoter might account for EMT and chemoresistant phenotype of these cells. Moreover, the invasiveness and proteinase activity of chemoresistant cells was greater, compared with sensitive cells. Interestingly, ETAR blockade with the specific ETAR antagonist, zibotentan, or its silencing with siRNA, reverted EMT, restored drug sensitivity to cytotoxic-induced apoptosis, and inhibited the invasive potential of resistant cells. In vivo, zibotentan inhibited tumor growth of sensitive and resistant EOC xenografts, and sensitized to chemotherapy. Finally, analysis of EOC tissues, with different responses to chemotherapy, revealed that ETAR is overexpressed in resistant tumors and is associated with EMT marker expression. All these data indicate that blockade of ETAR-driven EMT can overcome chemoresistance in EOC, improving the outcome of EOC patients’ treatment. Supported by AIRC Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 707. doi:10.1158/1538-7445.AM2011-707