NF-κB overrides the apoptotic program of TNF receptor 1 but not CD40 in carcinoma cells
NF-κB overrides the apoptotic program of TNF receptor 1 but not CD40 in carcinoma cells
复制标题
DOI：
10.1016/j.cellsig.2004.10.014
复制
发表时间：
2005-06-01
影响因子：
4.8
通讯作者：
Eliopoulos, AG
中科院分区：
文献类型：
--
作者：
Davies, CC;Bem, D;Eliopoulos, AG
tnf - α和TRAIL对nf - κ B和磷脂酰肌醇-3 （PI3）激酶的激活覆盖了这些配体在癌细胞中的促凋亡作用，阻碍了它们的治疗应用。在本报告中，我们表明CD40配体，TNF超家族的另一个成员，也触发这些信号通路的激活，但重要的是，仅利用PI3激酶级联进行抗凋亡反应，因为抑制PI3激酶而不是NF-kappa B使癌细胞对cd40l诱导的凋亡敏感。因此，NF-kappa B活化并不总是具有抗凋亡作用。此外，由于化学抑制剂对PI3激酶的特异性抑制不影响cd40介导的I κ B α磷酸化和降解或nf - κ B的结合和反激活，因此两种途径之间没有观察到串扰。同样，通过RNA干扰抑制Akt表达使细胞对cd40l诱导的凋亡敏感，但对cd40介导的I κ B α没有影响。退化。这些数据为NF-kappa B和PI3激酶/Akt在CD40连接介导的表型效应中的作用提供了新的证据，并突出了TNF家族成员调节癌细胞凋亡的机制差异。(c) 2004 Elsevier Inc.版权所有。
The activation of NF-kappa B and phosphatidylinositol-3 (PI3) kinase by TNF-alpha and TRAIL overrides the pro-apoptotic effects of these ligands in carcinoma cells and hinders their therapeutic application. In this report we show that CD40 ligand, another member of the TNF superfamily, also triggers the activation of these signalling pathways but, importantly, utilises only the PI3 kinase cascade for anti-apoptotic responses, inasmuch as suppression of PI3 kinase but not NF-kappa B sensitises carcinoma cells to CD40L-induced apoptosis. Therefore, NF-kappa B activation does not always confer anti-apoptotic effects. Moreover, no cross-talk between the two pathways was observed, as the specific suppression of PI3 kinase with chemical inhibitors did not influence CD40-mediated I kappa B alpha phosphorylation and degradation or NF-kappa B binding and transactivation. Similarly, whilst suppression of Akt expression by RNA interference sensitised rumour cells to CD40L-induced apoptosis, it had no effect on CD40-mediated I kappa B alpha. degradation. These data provide new evidence for the role of NF-kappa B and PI3 kinase/Akt in phenotypic effects mediated by CD40 ligation and highlight differences in the mechanisms by which TNF family members regulate apoptosis in carcinoma cells. (c) 2004 Elsevier Inc. All rights reserved.