Identification of a novel pro-apoptotic role of NF-κB in the regulation of TRAIL- and CD95-mediated apoptosis of glioblastoma cells
Identification of a novel pro-apoptotic role of NF-κB in the regulation of TRAIL- and CD95-mediated apoptosis of glioblastoma cells
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DOI：
10.1038/onc.2011.333
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发表时间：
2012-03-01
期刊：
影响因子：
8
通讯作者：
Fulda, S.
中科院分区：
文献类型：
--
作者：
Jennewein, C.;Karl, S.;Fulda, S.
我们最近报道，核因子 kappa B (NF-kappa B) 促进胶质母细胞瘤（最常见的脑肿瘤）中 DNA 损伤引发的细胞凋亡。在本研究中，我们研究了 NF-κ B 在死亡受体介导的细胞凋亡中的作用。在这里，我们确定了 NF-kappa B 在 TRAIL 和 CD95 诱导的细胞凋亡中的一种新的促凋亡功能。通过显性失活 I kappa B α 超阻遏物 (I kappa B α-SR) 过表达抑制 NF-kappa B 显着降低肿瘤坏死因子 (TNF) 相关凋亡诱导配体 (TRAIL) 或 CD95 诱导的细胞凋亡。反之亦然，通过过表达组成型活性 I kappa B 激酶复合物 (IKK)beta (IKK-EE) 激活 NF-kappa B 显着增加 TRAIL 介导的细胞凋亡。有趣的是，NF-κ B 抑制可减少 Fas 相关死亡结构域和 caspase-8 的募集以及刺激 TRAIL 受体或 CD95 时死亡诱导信号复合物 (DISC) 的形成。这导致表达 I kappa B α-SR 的细胞中 TRAIL 介导的半胱天冬酶激活减少、线粒体电位丧失和细胞色素 c 释放。相比之下，NF-κ B 抑制可强烈增强 TNF-α 介导的细胞凋亡。比较研究表明，TNF-α 快速刺激转录激活和抗凋亡蛋白上调，而 TRAIL 在转录激活之前引起细胞凋亡。因此，本研究首次证明 NF-kappa B 通过促进 DISC 形成，在 TRAIL 和 CD95 诱导的胶质母细胞瘤细胞凋亡中发挥促凋亡作用。癌基因 (2012) 31, 1468-1474; doi：10.1038/onc.2011.333； 2011 年 8 月 8 日在线发布
We recently reported that nuclear factor-kappa B (NF-kappa B) promotes DNA damage-triggered apoptosis in glioblastoma, the most common brain tumor. In the present study, we investigated the role of NF-kappa B in death receptor-mediated apoptosis. Here, we identify a novel pro-apopotic function of NF-kappa B in TRAIL- and CD95-induced apoptosis. Inhibition of NF-kappa B by overexpression of the dominant-negative I kappa B alpha-superrepressor (I kappa B alpha-SR) significantly decreases tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)- or CD95-induced apoptosis. Vice versa, activation of NF-kappa B via overexpression of constitutively active I kappa B kinase complex (IKK)beta (IKK-EE) significantly increases TRAIL-mediated apoptosis. Intriguingly, NF-kappa B inhibition reduces the recruitment of Fas-associated death domain and caspase-8 and formation of the death-inducing signaling complex (DISC) upon stimulation of TRAIL receptors or CD95. This results in reduced TRAIL-mediated activation of caspases, loss of mitochondrial potential and cytochrome c release in I kappa B alpha-SR-expressing cells. In comparison, NF-kappa B inhibition strongly enhances TNF-alpha-mediated apoptosis. Comparative studies revealed that TNF-alpha rapidly stimulates transcriptional activation and upregulation of anti-apoptotic proteins, whereas TRAIL causes apoptosis before transcriptional activation. Thus, this study demonstrates for the first time that NF-kappa B exerts a pro-apoptotic role in TRAIL- and CD95-induced apoptosis in glioblastoma cells by facilitating DISC formation. Oncogene (2012) 31, 1468-1474; doi:10.1038/onc.2011.333; published online 8 August 2011