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

John L. Herrmann, Alexander W. Beham, Mona Sarkiss, Paul J. Chiao, M. Todd Rands, Elizabeth M. Bruckheimer, Shawn Brisbay, Timothy J. McDonnell

Research output: Contribution to journalArticle

86 Scopus citations

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 IKBα 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-αB 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.

Original languageEnglish (US)
Pages (from-to)101-109
Number of pages9
JournalExperimental Cell Research
Volume237
Issue number1
DOIs
StatePublished - Nov 25 1997

Keywords

  • Apoptosis
  • Bcl-2
  • NF-κB
  • Prostate cancer
  • TNF-α

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'Bcl-2 suppresses apoptosis resulting from disruption of the NF-κB survival pathway'. Together they form a unique fingerprint.

  • Cite this