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

¹ Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute; ² Molecular Biology and Pathology Institute, National Research Council, Rome, Italy; ³ British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada; and ⁴ Unitat de Biologia Cellular i Molecular, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, Barcelona, Spain

Requests for reprints: Anna Bagnato, Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Via delle Messi D'Oro 156, 00158 Rome, Italy. Phone: 39-06-5266-2565; Fax: 39-06-5266-2600; E-mail: bagnato{at}ifo.it.

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_AR)/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_AR 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 ß-catenin, Snail, and other mesenchymal markers, and suppression of E-cadherin promoter activity. Activation of ET_AR by ET-1 triggers an integrin-linked kinase (ILK)–mediated signaling pathway leading to glycogen synthase kinase-3ß (GSK-3ß) inhibition, Snail and ß-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-3ß as well as Snail and ß-catenin protein stability, activity, and invasiveness, indicating that ET-1/ET_AR–induced EMT-promoting effects depend on ILK. ET_AR blockade by specific antagonists or reduction by ET_AR RNA interference reverses EMT and cell invasion by inhibiting autocrine signaling pathways. In ovarian carcinoma xenografts, ABT-627, a specific ET_AR antagonist, suppresses EMT determinants and tumor growth. In human ovarian cancers, ET_AR 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_AR axis during distinct steps of ovarian carcinoma progression and identify novel targets of therapeutic intervention. (Cancer Res 2005; 65(24): 11649-57)

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