Bcl-2 suppresses apoptosis resulting from disruption of the NF-kappa B survival pathway

Exp Cell Res. 1997 Nov 25;237(1):101-9. doi: 10.1006/excr.1997.3737.


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 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-kappa B in regulating TNF-alpha-induced apoptosis was investigated in prostate carcinoma cells. Enforced overexpression of bcl-2 protein in prostatic carcinoma cells impaired TNF-alpha-mediated cytotoxicity. Expression of bcl-2 did not impose a block to, or potentiate, TNF-alpha signaling of I kappa B alpha degradation, nuclear import of the RelA p65, or NF-kappa B-dependent transactivation. Expression of two dominant-negative I kappa B alpha mutant proteins significantly enhanced TNF-alpha-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-kappa B in these prostate carcinoma cells, also potentiated TNF-alpha-stimulated apoptosis signaling through a bcl-2-regulated mechanism. These findings indicate that modulation of NF-kappa B survival signaling may be used to clinical advantage in the treatment of prostate cancer patients. The efficacy of strategies 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antioxidants / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Cell Survival
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / metabolism
  • Humans
  • I-kappa B Proteins*
  • Kinetics
  • Male
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Proline / analogs & derivatives
  • Proline / pharmacology
  • 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
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Antineoplastic Agents
  • Antioxidants
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • Thiocarbamates
  • Tumor Necrosis Factor-alpha
  • prolinedithiocarbamate
  • NF-KappaB Inhibitor alpha
  • Proline