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 (ET(A)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(A)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 beta-catenin, Snail, and other mesenchymal markers, and suppression of E-cadherin promoter activity. Activation of ET(A)R by ET-1 triggers an integrin-linked kinase (ILK)-mediated signaling pathway leading to glycogen synthase kinase-3beta (GSK-3beta) 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-3beta as well as Snail and beta-catenin protein stability, activity, and invasiveness, indicating that ET-1/ET(A)R-induced EMT-promoting effects depend on ILK. 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, ABT-627, a specific ET(A)R antagonist, suppresses EMT determinants and tumor growth. In human ovarian cancers, ET(A)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(A)R axis during distinct steps of ovarian carcinoma progression and identify novel targets of therapeutic intervention.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Northern
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Blotting, Western
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Cadherins / genetics
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Cadherins / metabolism
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Cell Nucleus / metabolism
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Down-Regulation
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Endothelin A Receptor Antagonists
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Endothelin-1 / pharmacology*
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Enzyme Inhibitors
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Epithelial Cells / cytology*
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Female
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Gene Expression Regulation, Neoplastic*
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Genes, Dominant
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Luciferases / metabolism
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Mesoderm / cytology*
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Mesoderm / drug effects
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Mesoderm / metabolism
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Mice
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Mice, Nude
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Neoplasm Invasiveness
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism*
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Ovarian Neoplasms / pathology*
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Phenotype
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Phosphorylation
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Promoter Regions, Genetic / genetics
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Transport
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Receptor, Endothelin A / genetics
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Receptor, Endothelin A / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Snail Family Transcription Factors
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Transcription Factors / metabolism
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Transcription, Genetic
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Transfection
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
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beta Catenin / metabolism
Substances
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Cadherins
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Endothelin A Receptor Antagonists
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Endothelin-1
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Enzyme Inhibitors
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RNA, Messenger
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RNA, Small Interfering
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Receptor, Endothelin A
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Snail Family Transcription Factors
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Transcription Factors
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beta Catenin
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Luciferases
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integrin-linked kinase
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Protein Serine-Threonine Kinases
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Glycogen Synthase Kinase 3