Inhibition of Tumor Cell Proliferation by σ Ligands Is Associated with K+ Channel Inhibition and p27kip1 Accumulation

• Published in: The Journal of pharmacology and experimental therapeutics 2004-12, Vol.311 (3), p.1105
• Main Authors: Adrien Renaudo, Vanina Watry, Anne-Amandine Chassot, Gilles Ponzio, Jordi Ehrenfeld, Olivier Soriani
• Format: Article
• Language: English
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.104.072413

Previous studies have shown that σ receptors are overexpressed in tumor cells. However, the role of σ receptors remains enigmatic. Recently, we and others have demonstrated that σ-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 σ ligands on voltage-gated K + channels and cell proliferation. The σ 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 σ ligand-induced inhibition (10 μM) was igmesine = (+)-pentazocine > DTG, pointing to the involvement of σ-1 receptors. Addition of the K + channel blockers tetraethylammonium (TEA) and 4-aminopyridin or one of cited σ ligands in the culture media reversibly inhibited Jurkat cell growth. Interestingly, K + channel blockers and σ 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, σ ligands and TEA had no effect on caspase 3 activity. Accordingly, incubation of cells with σ ligands did not provoke DNA laddering. These data demonstrate that σ ligands and voltage-dependent channel blockers inhibit cell growth through a cell cycle arrest in the G 1 phase but not via an apoptotic mechanism. Altogether, these results indicate that the σ-1 receptor-induced inhibition of the cell cycle is, at least in part, the consequence of the inhibition of K + channels.