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Inhibition of TumorCell Proliferation byσ Ligands IsAssociated with K+Channel Inhibitionand p27kip1Accumulation Adrien RenaudoVanina WatryAnne‐Amandine Chassot2004 год

Inhibition of Tumor Cell Proliferation by σ Ligands Is Associated with K+ Channel Inhibition and p27kip1 Accumulation
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Аннотация: 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 p27kip1 and a decrease in cyclin A expression in Jurkat and SCLC cells, whereas no effect could be detected on p21cip1. 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 G1 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.
Год издания: 2004
Авторы: Adrien Renaudo, Vanina Watry, Anne‐Amandine Chassot, Gilles Ponzio, J. Ehrenfeld, Olivier Soriani
Издательство: American Society for Pharmacology and Experimental Therapeutics
Источник: Journal of Pharmacology and Experimental Therapeutics
Ключевые слова: Pharmacological Receptor Mechanisms and Effects, Sphingolipid Metabolism and Signaling, N-Heterocyclic Carbenes in Organic and Inorganic Chemistry
Другие ссылки: Journal of Pharmacology and Experimental Therapeutics (HTML)
PubMed (HTML)