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Bcl-2-Dependent Modulation of Swelling-Activated Cl^– Current and ClC-3 Expression in Human Prostate Cancer Epithelial Cells

Laboratoire de Physiologie Cellulaire, Institut National de la Santé et de la Recherche Médicale EMI 0228, Villeneuve d’Ascq, France

Cell shrinkage is an integral part of apoptosis. However, intimate mechanisms linking apoptotic events to the alterations in cell volume homeostasis remain poorly elucidated. We investigated how overexpression of Bcl-2 oncoprotein, a key antiapoptotic regulator, in lymph node carcinoma of the prostate (LNCaP) prostate cancer epithelial cells interferes with the volume-regulated anion channel (VRAC), a major determinant of regulatory volume decrease. Bcl-2 overexpression resulted in the doubling of VRAC-carried swelling-activated Cl^– current (I_Cl,swell) and weakened I_Cl,swell inhibition by store-operated Ca²⁺ channel (SOC)-transported Ca²⁺. This also was accompanied by substantial up-regulation of ClC-3 protein, a putative molecular candidate for the role of VRAC. ClC-3-specific antibody suppressed I_Cl,swell in the wild-type and Bcl-2-overexpressing LNCaP cells. Epidermal growth factor treatment of wild-type LNCaP cells, promoting their proliferation, resulted in the enhancement of endogenous Bcl-2 expression and associated increases in ClC-3 levels and I_Cl,swell magnitude. We conclude that Bcl-2-induced up-regulation of I_Cl,swell, caused by enhanced expression of ClC-3 and weaker negative control from SOC-transported Ca²⁺, would strengthen the ability of the cells to handle proliferative volume increases and thereby promote their survival and diminish their proapoptotic potential.

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