Bcl-2 antagonizes the combined apoptotic effect of transforming growth factor-beta and dihydrotestosterone in prostate cancer cells.
BACKGROUND
We previously demonstrated that dihydrotestosterone (DHT) enhances transforming growth factor-beta (TGF-beta) -induced apoptosis in human prostate cancer cells (Endocrinology 2001;142:2419-2426).


METHODS
In this study, the ability of the apoptosis suppressor bcl-2 to directly antagonize the combined apoptotic effect of TGF-beta and DHT in the androgen-sensitive LNCaP TbetaRII prostate cancer cells was examined. The previously cloned TGF-RbetaII receptor LNCaP cells, responsive to both TGF-beta and androgens, were engineered to overexpress the bcl-2 oncoprotein and the profile of apoptosis induction was analyzed in response to TGF-beta alone (5.0 ng/ml) or in combination with DHT (1 nM).


RESULTS
Biological characterization of cloned LNCaP TbetaRII hygromycin/bcl-2 transfectants demonstrated that bcl-2 overexpression resulted in a significant inhibition of the combined TGF-beta and DHT apoptotic effect in prostate cancer cells (P < 0.01). Furthermore, molecular analysis indicated that this antagonistic effect of bcl-2 on apoptosis was due to partial suppression of TGF-beta and DHT-mediated induction of caspase-1 expression and activation in LNCaP TbetaRII-hygro/bcl-2 transfectants. These results support a potential bcl-2 interference with the TGF-beta and androgen apoptotic signaling in prostate cancer cells by means of an antagonistic effect on caspase-1 activation.


CONCLUSIONS
This evidence may have mechanistic significance in understanding the contribution of bcl-2 overexpression in the development of androgen-independent prostate cancer by means of conferring resistance to TGF-beta-mediated apoptosis.
Bruckheimer
Elizabeth M
EM
Division of Urology, Department of Surgery, University of Maryland School of Medicine, Baltimore, USA.
Kyprianou
Natasha
N
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D020170:Caspase 1 / Q000096:biosynthesis; D013196:Dihydrotestosterone / Q000037:antagonists & inhibitors*; D019254:Genes, bcl-2 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D019253:Proto-Oncogene Proteins c-bcl-2; D016212:Transforming Growth Factor beta; D013196:Dihydrotestosterone; D020170:Caspase 1