MOLECULAR CORRELATES OF BCL-2-ENHANCED GROWTH FOLLOWING ANDROGEN-ABLATION IN PROSTATE CARCINOMA-CELLS IN-VIVO

Androgen-independent growth of prostate cancer is correlated with expr ession of bcl-2. The impact of bcl-2 expression on the growth of prost ate cancer cells following androgen ablation, was examined in the andr ogen-sensitive prostatic carcinoma cell line, LNCaP. Vector control an d bcl-2 expressing LNCaP cells were grown subcutaneously in male nude mice. Tumor volume, apoptosis, and proliferation were assessed followi ng castration. The levels of c-myc, p53, p21, bar, and bcl-2 protein w ere assessed by Western blotting. Bcl-2 expressing tumors exhibited a significant augmentation in growth compared to controls (p less than o r equal to 0.01). No difference in the spontaneous rate of proliferati on was observed between bcl-2 and control tumors, however, bcl-2 expre ssing tumors exhibited lower rates of apoptosis. Following orchiectomy the apoptotic index remained significantly lower in bcl-2 expressing tumors (p less than or equal to 0.002 at day 3). The proliferative ind ex was maintained in bcl-2 expressing, but not control tumors followin g castration. This resulted in a significant growth advantage in bcl-2 tumors subsequent to androgen ablation (p less than or equal to 0.001 ). These changes were accompanied by alterations in the levels of gene products known to regulate the cell cycle and/or apoptosis. These res ults emphasize the significance of bcl-2 expression during prostate ca ncer progression and suggest possible mechanisms for the acquisition o f androgen-independent tumor growth.