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CELLULAR AND MOLECULAR

Inhibition of Tumor Cell Proliferation by Ligands Is Associated with K⁺ Channel Inhibition and p27^kip1 Accumulation

University of Nice Sophia-Antipolis Centre National de la Recherche Scientifique Unité Mixte Recherche, Laboratoire de Physiologie des Membranes Cellulaires, Bt. Jean Maetz, La Darse, Chemin du Lazaret, Villefranche-sur-Mer, France (A.R., V.W., J.E., O.S.); and Institut National de la Santé et de la Recherche Médicale U385, Biology and Physiology of the Skin, Faculté de Médecine, Nice Cedex, France (A.-A.C.)

Previous studies have shown that receptors are overexpressed in tumor cells. However, the role of receptors remains enigmatic. Recently, we and others have demonstrated that -1 receptor modulates K⁺ channels in pituitary. In the present report, patch-clamp and Western blot assays were used in small cell lung cancer (SCLC, NCI-H209, and NCI-H146) and leukemic (Jurkat) cell lines to investigate the effects of ligands on voltage-gated K⁺ channels and cell proliferation. The ligands (+)-pentazocine, igmesine, and 1,3-di(2-tolyl)guanidine (DTG) all reversibly inhibited voltage-activated K⁺ currents in both cell lines. The potency of ligand-induced inhibition (10 µM) was igmesine = (+)-pentazocine > DTG, pointing to the involvement of -1 receptors. Addition of the K⁺ channel blockers tetraethylammonium (TEA) and 4-aminopyridin or one of cited ligands in the culture media reversibly inhibited Jurkat cell growth. Interestingly, K⁺ channel blockers and ligands caused an accumulation of the cyclin-dependent kinase inhibitor p27^kip1 and a decrease in cyclin A expression in Jurkat and SCLC cells, whereas no effect could be detected on p21^cip1. Moreover, ligands and TEA had no effect on caspase 3 activity. Accordingly, incubation of cells with ligands did not provoke DNA laddering. These data demonstrate that ligands and voltage-dependent channel blockers inhibit cell growth through a cell cycle arrest in the G₁ phase but not via an apoptotic mechanism. Altogether, these results indicate that the -1 receptor-induced inhibition of the cell cycle is, at least in part, the consequence of the inhibition of K⁺ channels.

Address correspondence to: Dr. Olivier Soriani, UNSA Centre National de la Recherche Scientifique UMR 6078, Laboratoire de Physiologie des Membranes Cellulaires, Bt. Jean Maetz, La Darse, 284, Chemin du Lazaret, 06230 Villefranche-sur-Mer, France. E-mail: soriani{at}obs-vlfr.fr

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