Fiche publication
Date publication
mars 2012
Auteurs
Membres identifiés du Cancéropôle Est :
Dr MICHEAU Olivier
Tous les auteurs :
Jennewein C, Karl S, Baumann B, Micheau O, Debatin KM, Fulda S
Lien Pubmed
Résumé
We recently reported that nuclear factor-kappa B (NF-kappaB) promotes DNA damage-triggered apoptosis in glioblastoma, the most common brain tumor. In the present study, we investigated the role of NF-kappaB in death receptor-mediated apoptosis. Here, we identify a novel pro-apopotic function of NF-kappaB in TRAIL- and CD95-induced apoptosis. Inhibition of NF-kappaB by overexpression of the dominant-negative IkappaBalpha-superrepressor (IkappaBalpha-SR) significantly decreases tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)- or CD95-induced apoptosis. Vice versa, activation of NF-kappaB via overexpression of constitutively active IkappaB kinase complex (IKK)beta (IKK-EE) significantly increases TRAIL-mediated apoptosis. Intriguingly, NF-kappaB 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 IkappaBalpha-SR-expressing cells. In comparison, NF-kappaB 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-kappaB exerts a pro-apoptotic role in TRAIL- and CD95-induced apoptosis in glioblastoma cells by facilitating DISC formation.
Référence
Oncogene. 2012 Mar 15;31(11):1468-74
