Acquisition of Chemoresistance and EMT Phenotype Is Linked with Activation of the Endothelin A Receptor Pathway in Ovarian Carcinoma Cells

作者：Rosano Laura; Cianfrocca Roberta; Spinella Francesca; Di Castro Valeriana; Nicotra Maria Rita; Lucidi Alessandro; Ferrandina Gabriella; Natali Pier Giorgio; Bagnato Anna^*

来源：Clinical Cancer Research, 2011, 17(8): 2350-2360.

DOI：10.1158/1078-0432.CCR-10-2325

Purpose: Emerging evidence suggests molecular and phenotypic association between chemoresistance and epithelial-mesenchymal transition (EMT) in cancer. Endothelin-1 (ET-1)/endothelin A receptor (ETAR) axis is implicated in the pathobiology of epithelial ovarian cancer (EOC) by driving tumor-promoting effects, including EMT. Here, we analyzed how ETAR regulates chemoresistance and EMT in EOC.
Experimental Design: The effects of ET-1 axis on cell proliferation, drug-induced apoptosis, invasiveness, and EMT were analyzed in cultured EOC cells sensitive and resistant to cisplatinum and taxol. Tumor growth in response to ETAR antagonist was examined in EOC xenografts. ETAR expression was examined in 60 human EOC tumors by immunohistochemistry and correlated with chemoresistance and EMT.
Results: In resistant EOC cells ET-1 and ETAR are upregulated, paralleled by enhanced mitogen activated protein kinase (MAPK) and Akt phosphorylation and cell proliferation. Moreover, in these cells the expression of E-cadherin transcriptional repressors, including Snail, Slug, and Twist, as well as of mesenchymal markers, such as vimentin and N-cadherin, were upregulated and linked with enhanced invasive behavior. Interestingly, ETAR blockade with zibotentan, a specific ETAR antagonist, or its silencing, downregulated Snail activity, restored drug sensitivity to cytotoxic-induced apoptosis, and inhibited the invasiveness of resistant cells. In vivo, zibotentan inhibited tumor growth of sensitive and resistant EOC xenografts, and sensitized to chemotherapy. Analysis of EOC human tissues revealed that ETAR is overexpressed in resistant tumors and is associated with EMT phenotype.
Conclusions: Our data provide the first evidence that blockade of ETAR-driven EMT can overcome chemoresistance and inhibit tumor progression, improving the outcome of EOC patients' treatment. Clin Cancer Res; 17(8); 2350-60.

• 出版日期2011-4-15