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J. Biol. Chem., Vol. 280, Issue 2, 1077-1085, January 14, 2005

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Integrin-mediated Adhesion and Soluble Ligand Binding Stabilize COX-2 Protein Levels in Endothelial Cells by Inducing Expression and Preventing Degradation^*

Jelena Zaric and Curzio Rüegg

From the Centre Pluridisciplinaire d'Oncologie (CePO) and Swiss Institute for Experimental Cancer Research (ISREC), National Center of Competence in Research (NCCR) Molecular Oncology, CH-1066 Epalinges s/Lausanne, Switzerland

Cyclooxygenase-2 (COX-2), a key enzyme in prostaglandin synthesis, is highly expressed during inflammation and cellular transformation and promotes tumor progression and angiogenesis. We have previously demonstrated that endothelial cell COX-2 is required for integrin _V3-dependent activation of Rac-1 and Cdc-42 and for endothelial cell spreading, migration, and angiogenesis (Dormond, O., Foletti, A., Paroz, C., and Ruegg, C. (2001) Nat. Med. 7, 1041–1047; Dormond, O., Bezzi, M., Mariotti, A., and Ruegg, C. (2002) J. Biol. Chem. 277, 45838–45846). In this study, we addressed the question of whether integrin-mediated cell adhesion may regulate COX-2 expression in endothelial cells. We report that cell detachment from the substrate caused rapid degradation of COX-2 protein in human umbilical vein endothelial cells (HUVEC) independent of serum stimulation. This effect was prevented by broad inhibition of cellular proteinases and by neutralizing lysosomal activity but not by inhibiting the proteasome. HUVEC adhesion to laminin, collagen I, fibronectin, or vitronectin induced rapid COX-2 protein expression with peak levels reached within 2 h and increased COX-2-dependent prostaglandin E₂ production. In contrast, nonspecific adhesion to poly-L-lysine was ineffective in inducing COX-2 expression. Furthermore, the addition of matrix proteins in solution promoted COX-2 protein expression in suspended or poly-L-lysine-attached HUVEC. Adhesion-induced COX-2 expression was strongly suppressed by pharmacological inhibition of c-Src, phosphatidylinositol 3-kinase, p38, extracellular-regulated kinase 1/2, and, to a lesser extent, protein kinase C and by the inhibition of mRNA or protein synthesis. In conclusion, this work demonstrates that integrin-mediated cell adhesion and soluble integrin ligands contribute to maintaining COX-2 steady-state levels in endothelial cells by the combined prevention of lysosomal-dependent degradation and the stimulation of mRNA synthesis involving multiple signaling pathways.

Received for publication, August 31, 2004 , and in revised form, November 2, 2004.

^* This work was supported in part by a grant from the Swiss National Science Foundation (31-63752.00), by the NCCR Molecular Oncology, a research instrument of the Swiss National Science Foundation, and by the CORE Award from Pfizer Oncology. 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.

To whom correspondence should be addressed: Centre Pluridisciplinaire d'Oncologie, Swiss Institute for Experimental Cancer Research (ISREC), 155 Chemin des Boveresses, CH1066 Epalinges, Switzerland. Tel.: 41-21-692-5853; Fax: 41-21-692-5872; E-mail: curzio.ruegg{at}isrec.ch.

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