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 language | English (US) |
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Pages (from-to) | 101-109 |
Number of pages | 9 |
Journal | Experimental Cell Research |
Volume | 237 |
Issue number | 1 |
DOIs | |
State | Published - Nov 25 1997 |
Keywords
- Apoptosis
- Bcl-2
- NF-κB
- Prostate cancer
- TNF-α
ASJC Scopus subject areas
- Cell Biology