Cancer cell cycle modulated by a functional coupling between sigma-1 receptors and Cl- channels.
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| Abstract |
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-transfected 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.
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| Authors | Adrien Renaudo, Sébastien L'Hoste, Hélène Guizouarn, Franck Borgèse, Olivier Soriani |
| Journal | The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 4 Pg. 2259-67 (Jan 26 2007) ISSN: 0021-9258 [Print] United States |
| PMID | 17121836 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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