Alterations in the regulatory volume decrease (RVD) and swelling-activated Cl- current associated with neuroendocrine differentiation of prostate cancer epithelial cells

Neuroendocrine (NE) differentiation of prostate epithelial/basal cells is a hallmark of advanced, androgen-independent prostate cancer, for which there is no successful therapy. Here we report for the first time on alterations in regulatory volume decrease (RVD) and its key determinant, swelling-activated Cl- current (I-Cl,I-swell), associated with NE differentiation of androgen-dependent LNCaP prostate cancer epithelial cells. NE-differentiating regimens, namely, chronic CAMP elevation or androgen deprivation, resulted in generally augmented I-Cl,I-swell and enhanced RVD. This occurred as a result of both the increased endogenous expression of CIC-3, which is a volume-sensitive Cl- channel involved, as we show, in I-Cl,I-swell in LNCaP (lymph-node carcinoma of the prostate) cells and the weaker negative I-Cl,I-swell control from Ca2+ entering via store-dependent pathways. The changes in the RVD of NE-differentiated cells generally mimicked those reported for Bcl-2-conferred apoptotic resistance. Our results suggest that strengthening the mechanism that helps to maintain volume constancy may contribute to better survival rates of apoptosis-resistant NE cells.