Integrin-linked kinase functions as a downstream mediator of endothelin-1 to promote invasive behavior in ovarian carcinoma

Laura Rosanò, Francesca Spinella, Valeriana Di Castro, Shoukat Dedhar, Maria Rita Nicotra, Pier Giorgio Natali, Anna Bagnato

Research output: Contribution to journalArticle

Abstract

The endothelin-1 (ET-1) axis represents a novel target in several malignancies, including ovarian carcinoma. Upon being activated, the endothelin A receptor (ETAR) mediates multiple tumor-promoting activities, including mitogenesis, escape from apoptosis, angiogenesis, metastasis-related protease activation, epithelial-mesenchymal transition, and invasion. Integrin-linked kinase (ILK) is a multidomain focal adhesion protein that conveys intracellular signaling elicited by β1-integrin and growth factor receptors. In this study, we investigate whether the signaling triggered by ETAR leading to an aggressive phenotype is mediated by an ILK-dependent mechanism. In HEY and OVCA 433 ovarian carcinoma cell lines, activation of ETAR by ET-1 enhances the expression of α2β1 and α3β1 integrins. ILK activity increases as ovarian cancer cells adhere to type I collagen through β1 integrin signaling, and do so to a greater extent on ET-1 stimulation. ET-1 increases ILK mRNA and protein expression and activity in a time- and concentration-dependent manner. An ILK small-molecule inhibitor (KP-392) or transfection with a dominant-negative ILK mutant effectively blocks the phosphorylation of downstream signals. Akt and glycogen synthase kinase-3β. The blockade of ET-1/ETAR-induced ILK activity results in an inhibition of matrix metalloproteinase activation as well as of cell motility and invasiveness in a phosphoinositide 3 kinase-dependent manner. In ovarian carcinoma xenografts, ABT-627, a specific ETAR antagonist, suppresses ILK expression, Akt and glycogen synthase kinase-3β phosphorylation, and tumor growth. These data show that ILK functions as a downstream mediator of the ET-1/ETAR axis to potentiate aggressive cellular behavior. Thus, the ILK-related signaling cascade can be efficiently targeted by pharmacologic blockade of ETAR.

Original languageEnglish
Pages (from-to)833-842
Number of pages10
JournalMolecular Cancer Therapeutics
Volume5
Issue number4
DOIs
Publication statusPublished - Apr 2006

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

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