Abstract
In ovarian carcinoma, acquisition of invasiveness is accompanied by the loss of the epithelial features and the gain of a mesenchymal phenotype, a process known as epithelial-mesenchymal transition (EMT). The endothelin A receptor (ET<sub>A</sub>R)/endothelin-1 (ET-1) axis is overexpressed in primary and metastatic ovarian carcinoma. In this tumor type, the ET-1/ET<sub>A</sub>R axis has a critical role in ovarian carcinoma progression by inducing proliferation, survival, neoangiogenesis, loss of intercellular communication and invasion. Recently, we demonstrated that the ET-1/ET<sub>A</sub>R autocrine pathway drives EMT in ovarian tumor cells by inducing an invasive phenotype through downregulation of E-cadherin, increased levels of β-catenin, Snail and other mesenchymal markers, and suppression of E-cadherin promoter activity. Activation of ET<sub>A</sub>R by ET-1 triggers a phosphatidylinositol 3-kinase-dependent integrin-linked kinase (ILK)-mediated signaling pathway leading to glycogen synthase kinase-3β (GSK-3β) inhibition, Snail and β-catenin stabilization andtranscriptional 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, transcriptional activity and invasiveness, indicating that ET-1/ET<sub>A</sub>R-induced EMT depends on ILK activity. 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, the specific ET<sub>A</sub>R antagonist ABT-627 suppresses EMT determinants and tumor growth. In human ovarian cancers, ET<sub>A</sub>R expression is associated with E-cadherin downregulation, N-cadherin expression and tumor grade. In conclusion, our findings demonstrate that ET<sub>A</sub>R activation by ET-1 is a key mechanism of the complex signaling network that promotes EMT as well as ovarian cancer cell invasion. The small molecule ET<sub>A</sub>R antagonist achieves concomitant suppression of tumor growth and EMT effectors, providing a new opportunity for therapeutic intervention in which targeting ILK pathway and the related Snail and β-catenin signaling cascade via ET<sub>A</sub>R blockade may be advantageous in the treatment of ovarian cancer.
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