Ca2+ homeostasis and apoptotic resistance of neuroendocrine-differentiated prostate cancer cells.
Neuroendocrine (NE) differentiation is a hallmark of advanced, androgen-independent prostate cancer, for which there is no successful therapy. NE tumor cells are nonproliferating and escape apoptotic cell death; therefore, an understanding of the apoptotic status of the NE phenotype is imperative for the development of new therapies for prostate cancer. Here, we report for the first time on alterations in intracellular Ca(2+) homeostasis, which is a key factor in apoptosis, caused by NE differentiation of androgen-dependent prostate cancer epithelial cells. NE-differentiating regimens, either cAMP elevation or androgen deprivation, resulted in a reduced endoplasmic reticulum Ca(2+)-store content due to both SERCA 2b Ca(2+) ATPase and luminal Ca(2+) binding/storage chaperone calreticulin underexpression, and to a downregulated store-operated Ca(2+) current. NE-differentiated cells showed enhanced resistance to thapsigargin- and TNF-alpha-induced apoptosis, unrelated to antiapoptotic Bcl-2 protein overexpression. Our results suggest that targeting the key players determining Ca(2+) homeostasis in an attempt to enhance the proapoptotic potential of malignant cells may prove to be a useful strategy in the treatment of advanced prostate cancer.
Vanoverberghe
K
K
Laboratoire de Physiologie Cellulaire, INSERM EMI 0228, Université des Sciences et Technologies de Lille, Bât. SN3, Villeneuve d'Ascq 59655, France.
Vanden Abeele
F
F
Mariot
P
P
Lepage
G
G
Roudbaraki
M
M
Bonnal
J L
JL
Mauroy
B
B
Shuba
Y
Y
Skryma
R
R
Prevarskaya
N
N
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D025802:Electric Capacitance; D017097:Electric Impedance; D004594:Electrophysiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005456:Fluorescent Dyes; D016257:Fura-2; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D009490:Neurosecretory Systems; D018408:Patch-Clamp Techniques; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015220:Calcium Channels; D037282:Calreticulin; D005456:Fluorescent Dyes; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases; D002118:Calcium; D016257:Fura-2