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

• Published in: Experimental cell research 1997-11, Vol.237 (1), p.101-109
• Main Authors: Herrmann, John L., Beham, Alexander W., Sarkiss, Mona, Chiao, Paul J., Rands, M.Todd, Bruckheimer, Elizabeth M., Brisbay, Shawn, McDonnell, Timothy J.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antioxidants - pharmacology; apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Bcl-2; Cell Survival; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - metabolism; Humans; I-kappa B Proteins; Kinetics; Male; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; NF-κB; Proline - analogs & derivatives; Proline - pharmacology; prostate cancer; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Proto-Oncogene Proteins c-bcl-2 - physiology; Recombinant Fusion Proteins - biosynthesis; Recombinant Proteins - pharmacology; Signal Transduction; Thiocarbamates - pharmacology; TNF-α; Transfection; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1006/excr.1997.3737

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.