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, HEKtransfected 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.Sigma receptors are intracellular proteins that were first postulated as opioid receptors on the basis of pharmacological and behavioral studies (1). Finally, 20 years of pharmacological studies and the cloning of the sigma-1 receptor subtype in 1996 revealed indeed that the "sigma-binding site" corresponded to a 24-kDa protein unrelated to other mammalian proteins and localized in the inner face of the plasma membrane and the membranes of the endoplasmic reticulum and the nucleus (2-5). Although high concentrations of neurosteroids have been shown to interact with brain sigma-1 receptors in behavioral studies (for review see Ref. 6), no high affinity endogene sigma ligand has been identified yet. Nonetheless, exogene compounds from disparate chemical classes ((ϩ)-benzomorphans, cocaine, guanidines, and neuroleptics for example) have been characterized or developed as highly selective sigma ligands (7). The sigma-1 receptors are expressed in various tissues including the brain, the pituitary, and the liver (2, 8 -10). Surprisingly, very high levels of sigma receptors have been detected in tumor cells when compared with normal cells (11,12). Indeed, the expression of sigma receptors in cancer biopsies is correlated with the proliferating state of the cells so that these proteins are now commonly considered to be tumor biomarkers (13,14). Consequently, many sigma ligands are developed nowadays for imagery (positon emission tomography scan) to detect early stage tumors (15, 16). However, if sigma receptors represent exciting targets to detect cancers in vivo, very few data are available on both the function and the action m...
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 ϩ 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 ϩ channels and cell proliferation. The ligands (ϩ)-pentazocine, igmesine, and 1,3-di(2-tolyl)guanidine (DTG) all reversibly inhibited voltage-activated K ϩ currents in both cell lines. The potency of ligand-induced inhibition (10 M) was igmesine ϭ (ϩ)-pentazocine Ͼ DTG, pointing to the involvement of -1 receptors. Addition of the K ϩ channel blockers tetraethylammonium (TEA) and 4-aminopyridin or one of cited ligands in the culture media reversibly inhibited Jurkat cell growth. Interestingly, K ϩ 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 G 1 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 ϩ channels.
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