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Endothelin Receptor Type B Counteracts Tenascin-C–Induced Endothelin Receptor Type A–Dependent Focal Adhesion and Actin Stress Fiber Disorganization

¹ Center for Biomedicine, Department of Clinical and Biological Sciences and ² Institute of Pathology, University of Basel, Basel, Switzerland; ³ Laboratory of Tumor Biology and Genetics, Neurosurgery, University Hospital Lausanne, Lausanne, Switzerland; ⁴ National Center of Competence in Research (NCCR) in Molecular Oncology, Swiss Institute for Experimental Cancer Research, Epalinges sur Lausanne, Switzerland; ⁵ Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; and ⁶ Department of Obstetrics and Gynecology, Münster University Hospital, Münster, Germany

Requests for reprints: Gertraud Orend, Center for Biomedicine, Department of Clinical and Biological Sciences, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland. Phone: 41-61-267-35-41; Fax: 41-61-267-35-66; E-mail: gertraud.orend{at}unibas.ch.

Tenascin-C, an extracellular matrix molecule of the tumor-specific microenvironment, counteracts the tumor cell proliferation–suppressing effect of fibronectin by blocking the integrin ₅ß₁/syndecan-4 complex. This causes cell rounding and stimulates tumor cell proliferation. Tenascin-C also stimulates endothelin receptor type A (EDNRA) expression. Here, we investigated whether signaling through endothelin receptors affects tenascin-C–induced cell rounding. We observed that endothelin receptor type B (EDNRB) activation inhibited cell rounding by tenascin-C and induced spreading by restoring expression and function of focal adhesion kinase (FAK), paxillin, RhoA, and tropomyosin-1 (TM1) via activation of epidermal growth factor receptor, phospholipase C, c-Jun NH₂-terminal kinase, and the phosphatidylinositol 3-kinase pathway. In contrast to EDNRB, signaling through EDNRA induced cell rounding, which correlated with FAK inhibition and TM1 and RhoA protein destabilization in the presence of tenascin-C. This occurred in a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase–dependent manner. Thus, tumorigenesis might be enhanced by tenascin-C involving EDNRA signaling. Inhibition of tenascin-C in combination with blocking both endothelin receptors could present a strategy for sensitization of cancer and endothelial cells toward anoikis. [Cancer Res 2007;67(13):6163–73]

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