Data from Endothelin-1 Promotes Epithelial-to-Mesenchymal Transition in Human Ovarian Cancer Cells

Abstract

<div>Abstract<p>Despite considerable efforts to improve early detection and advances in chemotherapy, metastatic relapses remain a major challenge in the management of ovarian cancer. The endothelin A receptor (ET<sub>A</sub>R)/endothelin-1 (ET-1) axis has been shown to have a significant role in ovarian carcinoma by promoting tumorigenesis. Here we show that the ET-1/ET<sub>A</sub>R autocrine pathway drives epithelial-to-mesenchymal transition (EMT) in ovarian tumor cells by inducing a fibroblastoid and invasive phenotype, down-regulation of E-cadherin, increased levels of β-catenin, <i>Snail</i>, and other mesenchymal markers, and suppression of E-cadherin promoter activity. Activation of ET<sub>A</sub>R by ET-1 triggers an integrin-linked kinase (ILK)–mediated signaling pathway leading to glycogen synthase kinase-3β (GSK-3β) inhibition, Snail and β-catenin stabilization, and regulation of transcriptional programs that control EMT. Transfection of dominant negative ILK or exposure to an ILK inhibitor suppresses the ET-1-induced phosphorylation of GSK-3β as well as Snail and β-catenin protein stability, activity, and invasiveness, indicating that ET-1/ET<sub>A</sub>R–induced EMT-promoting effects depend on ILK. ET<sub>A</sub>R blockade by specific antagonists or reduction by ET<sub>A</sub>R RNA interference reverses EMT and cell invasion by inhibiting autocrine signaling pathways. In ovarian carcinoma xenografts, ABT-627, a specific ET<sub>A</sub>R antagonist, suppresses EMT determinants and tumor growth. In human ovarian cancers, ET<sub>A</sub>R expression is associated with E-cadherin down-regulation, N-cadherin expression, and tumor grade. Collectively, these findings provide evidence of a critical role for the ET-1/ET<sub>A</sub>R axis during distinct steps of ovarian carcinoma progression and identify novel targets of therapeutic intervention. (Cancer Res 2005; 65(24): 11649-57)</p></div>