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[摘要]：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 |
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