Endothelin receptor type B counteracts tenascin-C-induced endothelin receptor type A-dependent focal adhesion and actin stress fiber disorganization

• Published in: Cancer research (Chicago, Ill.) Ill.), 2007-07, Vol.67 (13), p.6163-6173
• Main Authors: LANGE, Katrin, KAMMERER, Martial, OREND, Gertraud, HEGI, Monika E, GROTEGUT, Stefan, DITTMANN, Antje, WENTAO HUANG, FLURI, Erika, YIP, George W, GÖTTE, Martin, RUIZ, Christian
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Antineoplastic agents; Biological and medical sciences; Brain Neoplasms - metabolism; Cell Adhesion; Cell Proliferation; Cytoskeleton - metabolism; Focal Adhesions; Gene Expression Regulation, Neoplastic; Glioma - metabolism; Humans; Kinetics; Medical sciences; Pharmacology. Drug treatments; Receptor, Endothelin A - metabolism; Receptor, Endothelin A - physiology; Receptor, Endothelin B - metabolism; Receptor, Endothelin B - physiology; Signal Transduction; Stress Fibers - metabolism; Tenascin - biosynthesis; Tenascin - metabolism; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-06-3348

Tenascin-C, an extracellular matrix molecule of the tumor-specific microenvironment, counteracts the tumor cell proliferation-suppressing effect of fibronectin by blocking the integrin alpha(5)beta(1)/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 NH(2)-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.