Epithelial-Mesenchymal Transition in Ovarian Cancer Progression: A Crucial Role for the Endothelin Axis

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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(A)R)/endothelin-1 (ET-1) axis is overexpressed in primary and metastatic ovarian carcinoma. In this tumor type, the ET-1/ET(A)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(A)R autocrine pathway drives EMT in ovarian tumor cells by inducing an invasive phenotype through downregulation of E-cadherin, increased levels of beta-catenin, Snail and other mesenchymal markers, and suppression of E-cadherin promoter activity. Activation of ET(A)R by ET-1 triggers a phosphatidylinositol 3-kinase-dependent integrin-linked kinase (ILK)-mediated signaling pathway leading to glycogen synthase kinase-3beta (GSK-3beta) inhibition, Snail and beta-catenin stabilization and transcriptional programs that control EMT. Transfection of dominant negative ILK or exposure to an ILK inhibitor suppresses the ET-1-induced phosphorylation of GSK-3beta as well as Snail and beta-catenin protein stability, transcriptional activity and invasiveness, indicating that ET-1/ET(A)R-induced EMT depends on ILK activity. ET(A)R blockade by specific antagonists, or reduction by ET(A)R RNA interference, reverses EMT and cell invasion by inhibiting autocrine signaling pathways. In ovarian carcinoma xenografts, the specific ET(A)R antagonist ABT-627 suppresses EMT determinants and tumor growth. In human ovarian cancers, ET(A)R expression is associated with E-cadherin downregulation, N-cadherin expression and tumor grade. In conclusion, our findings demonstrate that ET(A)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(A)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 beta-catenin signaling cascade via ET(A)R blockade may be advantageous in the treatment of ovarian cancer.