Bcl-2-dependent modulation of swelling-activated Cl- current and ClC-3 expression in human prostate cancer epithelial cells

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,I-swell) and weakened I-Cl,I-swell inhibition by store-operated Ca2+ channel (SOC)transported Ca2+. This also was accompanied by substantial up-regulation of CIC-3 protein, a putative molecular candidate for the role of VRAC. CIC-3-specific antibody suppressed I-Cl,I-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 CIC-3 levels and I-Cl,I-swell magnitude. We conclude that Bcl-2-induced up-regulation of I-Cl,I-swell caused by enhanced expression of CIC-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.