BCL-2 SUPPRESSES APOPTOSIS RESULTING FROM DISRUPTION OF THE NF-KAPPA-B SURVIVAL PATHWAY

A role has been delineated for both bcl-2 and NF-kappa B in mediating an adaptive survival response to the TNF-alpha signaling pathway for a poptosis. Additionally, we and others have demonstrated a role for bcl -2 upregulation during progression of prostate cancer and acquisition of androgen-independent growth (T. J. McDonnell et al., 1992, Cancer R es. 52, 6940-6944). Therefore, the relationship between bcl-2 and NF-k appa B in regulating TNF-alpha-induced apoptosis was investigated in p rostate carcinoma cells. Enforced overexpression of bcl-2 protein in p rostatic carcinoma cells impaired TNF-alpha-mediated cytotoxicity, Exp ression of bcl-2 did not impose a block to, or potentiate, TNF-alpha s ignaling of I kappa B alpha degradation, nuclear import of the RelA p6 5, or NF-kappa B-dependent transactivation. Expression of two dominant -negative I kappa B alpha mutant proteins significantly enhanced TNF-a lpha-induced apoptosis in control cells but not in cells expressing hi gh levels of bcl-2 protein, Similarly, PDTC, a strong antioxidant that interferes with activation of NF-kappa B in these prostate carcinoma cells, also potentiated TNF-alpha-stimulated apoptosis signaling throu gh a bcl-2-regulated mechanism. These findings indicate that modulatio n of NF-kappa B survival signaling may be used to clinical advantage i n the treatment of prostate cancer patients. The efficacy of strategie s proposed to enhance TNF-alpha-mediated cytotoxicity by inhibiting NF -kappa B will likely be influenced by context-dependent variables such as bcl-2 expression. (C) 1997 Academic Press.