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 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.
Herrmann
J L
JL
Department of Molecular Pathology, University of Texas, M. D. Anderson Cancer Center, Houston 77030, USA.
Beham
A W
AW
Sarkiss
M
M
Chiao
P J
PJ
Rands
M T
MT
Bruckheimer
E M
EM
Brisbay
S
S
McDonnell
T J
TJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins; D007700:Kinetics; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011471:Prostatic Neoplasms; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D013859:Thiocarbamates / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; D000975:Antioxidants; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C066229:prolinedithiocarbamate; D000072000:NF-KappaB Inhibitor alpha; D011392:Proline