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Research Articles: Targets

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

¹ Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute; ² Molecular Biology and Pathology Institute, National Research Council, Rome, Italy; and ³ BC Cancer Research Centre, Vancouver, British Columbia, Canada

Requests for reprints: Anna Bagnato, Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Via delle Messi D'Oro 156, 00158 Rome, Italy. Phone: +39-65266-2565; Fax: +39-65266-2600. E-mail: bagnato{at}ifo.it

Abstract

The endothelin-1 (ET-1) axis represents a novel target in several malignancies, including ovarian carcinoma. Upon being activated, the endothelin A receptor (ET_AR) 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 ß1-integrin and growth factor receptors. In this study, we investigate whether the signaling triggered by ET_AR leading to an aggressive phenotype is mediated by an ILK-dependent mechanism. In HEY and OVCA 433 ovarian carcinoma cell lines, activation of ET_AR by ET-1 enhances the expression of ₂ß₁ and ₃ß₁ integrins. ILK activity increases as ovarian cancer cells adhere to type I collagen through ß₁ 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-3ß. The blockade of ET-1/ET_AR-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 ET_AR antagonist, suppresses ILK expression, Akt and glycogen synthase kinase-3ß phosphorylation, and tumor growth. These data show that ILK functions as a downstream mediator of the ET-1/ET_AR axis to potentiate aggressive cellular behavior. Thus, the ILK-related signaling cascade can be efficiently targeted by pharmacologic blockade of ET_AR. [Mol Cancer Ther 2006;5(4):833–42]

Grant support: Associazione Italiana per la Ricerca sul Cancro regional grant, Ministero della Salute, Consiglio Nazionale delle Ricerche, Ministero dell'Istruzione, dell'Università e della Ricerca.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12/14/05; revised 1/30/06; accepted 2/16/06.