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 (ETAR)/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/ETAR autocrine pathway drives epithelial-to-mesenchymal transition (EMT) in ovarian tumor cells by inducing a fibroblastoid and invasive phenotype, down-regulation of F-cadherin, increased levels of beta-catenin, Snail, and other mesenchymal markers, and suppression of E-cadherin promoter activity. Activation of ETAR by ET-1 triggers an integrin-linked kinase (ILK)-mediated signaling pathway leading to glycogen synthase kinase-3 beta (GSK-3 beta) inhibition, Snail and beta-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-3 beta as well as Snail and beta-catenin protein stability activity, and invasiveness, indicating that ET-1/ETAR-induced EMT-promoting effects depend on ILK. ETAR blockade by specific antagonists or reduction by ETAR RNA interference reverses EMT and cell invasion by inhibiting autocrine signaling pathways. In ovarian carcinoma xeno-grafts, ABT-627, a specific ETAR antagonist, suppresses EMT determinants and tumor growth. In human ovarian cancers, ETAR 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/ETAR axis during distinct steps of ovarian carcinoma progression anti identify novel targets of therapeutic intervention.
Endothelin-1 promotes epithelial-to-mesenchymal transition in human ovarian cancer cells
Spinella, Francesca;
2005-01-01
Abstract
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 (ETAR)/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/ETAR autocrine pathway drives epithelial-to-mesenchymal transition (EMT) in ovarian tumor cells by inducing a fibroblastoid and invasive phenotype, down-regulation of F-cadherin, increased levels of beta-catenin, Snail, and other mesenchymal markers, and suppression of E-cadherin promoter activity. Activation of ETAR by ET-1 triggers an integrin-linked kinase (ILK)-mediated signaling pathway leading to glycogen synthase kinase-3 beta (GSK-3 beta) inhibition, Snail and beta-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-3 beta as well as Snail and beta-catenin protein stability activity, and invasiveness, indicating that ET-1/ETAR-induced EMT-promoting effects depend on ILK. ETAR blockade by specific antagonists or reduction by ETAR RNA interference reverses EMT and cell invasion by inhibiting autocrine signaling pathways. In ovarian carcinoma xeno-grafts, ABT-627, a specific ETAR antagonist, suppresses EMT determinants and tumor growth. In human ovarian cancers, ETAR 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/ETAR axis during distinct steps of ovarian carcinoma progression anti identify novel targets of therapeutic intervention.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
