Bcl-2 Suppresses Apoptosis Resulting from Disruption of the NF-κB Survival Pathway

Abstract

A role has been delineated for both bcl-2 and NF-κB in mediating an adaptive survival response to the TNF-α signaling pathway for apoptosis. 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 Res.52, 6940–6944). Therefore, the relationship between bcl-2 and NF-κB in regulating TNF-α-induced apoptosis was investigated in prostate carcinoma cells. Enforced overexpression of bcl-2 protein in prostatic carcinoma cells impaired TNF-α-mediated cytotoxicity. Expression of bcl-2 did not impose a block to, or potentiate, TNF-α signaling of IκBα degradation, nuclear import of the RelA p65, or NF-κB-dependent transactivation. Expression of two dominant-negative IκBα mutant proteins significantly enhanced TNF-α-induced apoptosis in control cells but not in cells expressing high levels of bcl-2 protein. Similarly, PDTC, a strong antioxidant that interferes with activation of NF-κB in these prostate carcinoma cells, also potentiated TNF-α-stimulated apoptosis signaling through a bcl-2-regulated mechanism. These findings indicate that modulation of NF-κB survival signaling may be used to clinical advantage in the treatment of prostate cancer patients. The efficacy of strategies proposed to enhance TNF-α-mediated cytotoxicity by inhibiting NF-κB will likely be influenced by context-dependent variables such as bcl-2 expression.