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,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,swell) and enhanced RVD. This occurred as a result of both the increased endogenous expression of ClC-3, which is a volume-sensitive Cl- channel involved, as we show, in I(Cl,swell) in LNCaP (lymph-node carcinoma of the prostate) cells and the weaker negative I(Cl,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.
Lemonnier
L
L
Laboratoire de Physiologie Cellulaire, INSERM EMI 0228, USTL Bât. SN3, 59655 Villeneuve d'Ascq, France.
Lazarenko
R
R
Shuba
Y
Y
Thebault
S
S
Roudbaraki
M
M
Lepage
G
G
Prevarskaya
N
N
Skryma
R
R
D000728:Androgens / Q000502:physiology*; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D048429:Cell Size; D018118:Chloride Channels / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015854:Up-Regulation
D000728:Androgens; D018118:Chloride Channels; C115376:ClC-3 channel; D019253:Proto-Oncogene Proteins c-bcl-2; D002118:Calcium