Herrmann J L, Beham A W, Sarkiss M, Chiao P J, Rands M T, Bruckheimer E M, Brisbay S, McDonnell T J
Department of Molecular Pathology, University of Texas, M. D. Anderson Cancer Center, Houston 77030, USA.
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.
bcl-2和核因子κB在介导对肿瘤坏死因子α（TNF-α）凋亡信号通路的适应性生存反应中均发挥了作用。此外，我们及其他研究人员已证明bcl-2在前列腺癌进展及雄激素非依赖性生长过程中上调（T. J. 麦克唐奈等人，1992年，《癌症研究》52卷，6940 - 6944页）。因此，我们在前列腺癌细胞中研究了bcl-2与核因子κB在调节TNF-α诱导的凋亡中的关系。在前列腺癌细胞中强制过表达bcl-2蛋白会损害TNF-α介导的细胞毒性。bcl-2的表达并未阻止或增强IκBα降解、RelA p65核转运或核因子κB依赖性反式激活的TNF-α信号传导。两种显性负性IκBα突变蛋白的表达在对照细胞中显著增强了TNF-α诱导的凋亡，但在表达高水平bcl-2蛋白的细胞中则不然。同样，PDTC是一种强抗氧化剂，可干扰这些前列腺癌细胞中核因子κB的激活，它也通过bcl-2调节的机制增强了TNF-α刺激的凋亡信号传导。这些发现表明，调节核因子κB生存信号传导可能在前列腺癌患者的治疗中具有临床优势。通过抑制核因子κB来增强TNF-α介导的细胞毒性的策略的疗效可能会受到诸如bcl-2表达等依赖于背景的变量的影响。
