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J. Biol. Chem., Vol. 282, Issue 4, 2259-2267, January 26, 2007

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Cancer Cell Cycle Modulated by a Functional Coupling between Sigma-1 Receptors and Cl^– Channels^*

From the UNSA CNRS UMR 6548, Laboratoire de Physiologie Cellulaire & Moléculaire des Systèmes Intégrés, Université de Nice Sophia-Antipolis, 06108 Nice Cedex 2, France

The sigma-1 receptor is an intracellular protein characterized as a tumor biomarker whose function remains mysterious. We demonstrate herein for the first time that highly selective sigma ligands inhibit volume-regulated chloride channels (VRCC) in small cell lung cancer and T-leukemia cells. Sigma ligands and VRCC blockers provoked a cell cycle arrest underlined by p27 accumulation. In stably sigma-1 receptor-transfected HEK cells, the proliferation rate was significantly lowered by sigma ligands when compared with control cells. Sigma ligands produced a strong inhibition of VRCC in HEK-transfected cells but not in control HEK. Surprisingly, the activation rate of VRCC was dramatically delayed in HEK-transfected cells in the absence of ligands, indicating that sigma-1 receptors per se modulate cell regulating volume processes in physiological conditions. Volume measurements in hypotonic conditions revealed indeed that the regulatory volume decrease was delayed in HEK-transfected cells and virtually abolished in the presence of igmesine in both HEK-tranfected and T-leukemic cells. Moreover, HEK-transfected cells showed a significant resistance to staurosporine-induced apoptosis volume decrease, indicating that sigma-1 receptors protect cancer cells from apoptosis. Altogether, our results show for the first time that sigma-1 receptors modulate "cell destiny" through VRCC and cell volume regulation.

Received for publication, August 17, 2006 , and in revised form, November 6, 2006.

^* This work was supported by the Association Ti'Toine and l'Association de Recherche sur le Cancer. 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.

¹ Research fellow of the Ministère de l'Enseigement et de la Recherche.

² To whom correspondence should be addressed: Laboratoire de Physiologie Cellulaire & Moléculaire des Systèmes Intégrés, UNSA CNRS UMR 6548, Faculté des Sciences, Bâtiment de Sciences Naturelles, 3^ème étage, 28 avenue de Valrose, 06108 Nice Cedex 2, France. Tel.: 33-4-92-07-65-53; Fax: 33-4-92-07-68-34; E-mail: soriani{at}unice.fr.

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