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,swell)) and weakened I(Cl,swell) inhibition by store-operated Ca(2+) channel (SOC)-transported Ca(2+). 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 Ca(2+), would strengthen the ability of the cells to handle proliferative volume increases and thereby promote their survival and diminish their proapoptotic potential.
Lemonnier
Loïc
L
Laboratoire de Physiologie Cellulaire, INSERM EMI 0228, Université des Sciences et Technologies de Lille, Bâtiment SN3, 59655 Villeneuve d'Ascq, France.
Shuba
Yaroslav
Y
Crepin
Alexandre
A
Roudbaraki
Morad
M
Slomianny
Christian
C
Mauroy
Brigitte
B
Nilius
Bernd
B
Prevarskaya
Natalia
N
Skryma
Roman
R
D017209:Apoptosis / Q000502:physiology; D015220:Calcium Channels / Q000378:metabolism; D045744:Cell Line, Tumor; D048429:Cell Size / Q000502:physiology; D018118:Chloride Channels / Q000096:biosynthesis* / Q000235:genetics; D002712:Chlorides / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection
D015220:Calcium Channels; D018118:Chloride Channels; D002712:Chlorides; C115376:ClC-3 channel; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D004815:Epidermal Growth Factor