Cancer cell cycle modulated by a functional coupling between sigma-1 receptors and Cl- channels.
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.
Renaudo
Adrien
A
UNSA CNRS UMR 6548, Laboratoire de Physiologie Cellulaire & Moléculaire des Systèmes Intégrés, Université de Nice Sophia-Antipolis, 06108 Nice Cedex 2, France.
L'Hoste
Sébastien
S
Guizouarn
Hélène
H
Borgèse
Franck
F
Soriani
Olivier
O
D002452:Cell Count; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D048429:Cell Size; D018118:Chloride Channels / Q000378:metabolism*; D004594:Electrophysiology; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D017480:Receptors, sigma / Q000378:metabolism*; D000097605:Sigma-1 Receptor
D018118:Chloride Channels; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor