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Identification of a novel pro-apoptotic role of NF-κB in the regulation of TRAIL- and CD95-mediated apoptosis of glioblastoma cells

Oncogene volume 31, pages 1468–1474 (2012)Cite this article

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.

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Acknowledgements

We thank R Marienfeld (Ulm, Germany) for providing NEMO knockout mouse embryonic fibroblasts. This work has been partially supported by grants from the Deutsche Forschungsgemeinschaft, European Community (ApopTrain, APO-SYS) and IAP6/18 (to SF), and by a scholarship of the International Graduate School of Molecular Medicine Ulm University (to CJ).

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Authors and Affiliations

  1. University Children's Hospital, Ulm, Germany

    C Jennewein, S Karl, K-M Debatin & S Fulda

  2. Institute for Physiological Chemistry, Ulm University, Ulm, Germany

    B Baumann

  3. INSERM, U866, Dijon, France

    O Micheau

  4. Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany

    S Fulda

Authors
  1. C Jennewein
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  2. S Karl
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  3. B Baumann
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  4. O Micheau
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  5. K-M Debatin
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  6. S Fulda
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Correspondence to S Fulda.

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Supplementary Information accompanies the paper on the Oncogene website

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Jennewein, C., Karl, S., Baumann, B. et al. Identification of a novel pro-apoptotic role of NF-κB in the regulation of TRAIL- and CD95-mediated apoptosis of glioblastoma cells. Oncogene 31, 1468–1474 (2012). https://doi.org/10.1038/onc.2011.333

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