title: Identification of a novel pro-apoptotic role of NF-κB in the regulation of TRAIL- and CD95-mediated apoptosis of glioblastoma cells.
abstract: We recently reported that nuclear factor-kappa B (NF-κB) promotes DNA damage-triggered apoptosis in glioblastoma, the most common brain tumor. In the present study, we investigated the role of NF-κB in death receptor-mediated apoptosis. Here, we identify a novel pro-apopotic function of NF-κB in TRAIL- and CD95-induced apoptosis. Inhibition of NF-κB by overexpression of the dominant-negative IκBα-superrepressor (IκBα-SR) significantly decreases tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)- or CD95-induced apoptosis. Vice versa, activation of NF-κB via overexpression of constitutively active IκB kinase complex (IKK)β (IKK-EE) significantly increases TRAIL-mediated apoptosis. Intriguingly, NF-κB 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 IκBα-SR-expressing cells. In comparison, NF-κB inhibition strongly enhances TNF-α-mediated apoptosis. Comparative studies revealed that TNF-α 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-κB exerts a pro-apoptotic role in TRAIL- and CD95-induced apoptosis in glioblastoma cells by facilitating DISC formation.
authors.affiliation: University Children's Hospital, Ulm, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Jennewein
authors.forename: S
authors.initials: S
authors.lastname: Karl
authors.forename: B
authors.initials: B
authors.lastname: Baumann
authors.forename: O
authors.initials: O
authors.lastname: Micheau
authors.forename: K-M
authors.initials: KM
authors.lastname: Debatin
authors.forename: S
authors.initials: S
authors.lastname: Fulda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000378:metabolism*; D020169:Caspases; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015533:Transcriptional Activation; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; D019014:fas Receptor; D020169:Caspases