bcl-2 antagonizes the combined apoptotic effect of transforming growth factor-? and dihydrotestosterone in prostate cancer cells

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Abstract
BACKGROUND We previously demonstrated that dihydrotestosterone (DHT) enhances transforming growth factor-β (TGF-β) -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-β and DHT in the androgen-sensitive LNCaP TβRII prostate cancer cells was examined. The previously cloned TGF-RβII receptor LNCaP cells, responsive to both TGF-β and androgens, were engineered to overexpress the bcl-2 oncoprotein and the profile of apoptosis induction was analyzed in response to TGF-β alone (5.0 ng/ml) or in combination with DHT (1 nM). RESULTS Biological characterization of cloned LNCaP TβRII hygromycin/bcl-2 transfectants demonstrated that bcl-2 overexpression resulted in a significant inhibition of the combined TGF-β 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-β and DHT-mediated induction of caspase-1 expression and activation in LNCaP TβRII-hygro/bcl-2 transfectants. These results support a potential bcl-2 interference with the TGF-β and androgen apoptotic signaling in prostate cancer cells by means of an antagonistic effect on caspase-1 activation. CONCLUSION 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-β–mediated apoptosis. Prostate 53: 133–142, 2002.