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NF-κB-independent sensitization of glioblastoma cells for TRAIL-induced apoptosis by proteasome inhibition

La Ferla-Brühl, K and Westhoff, MA and Karl, S and Kasperczyk, H and Zwacka, RM and Debatin, KM and Fulda, S (2007) 'NF-κB-independent sensitization of glioblastoma cells for TRAIL-induced apoptosis by proteasome inhibition.' Oncogene, 26 (4). 571 - 582. ISSN 0950-9232

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Abstract

The transcription factor nuclear factor-kappaB (NF-κB) is a key regulator of stress-induced transcriptional activation and has been implicated in mediating primary or acquired apoptosis resistance in various cancers. In the present study, we therefore investigated the role of NF-κB in regulating apoptosis in malignant glioma, a prototypic tumor refractory to current treatment approaches. Here, we report that constitutive NF-κB DNA-binding activity was low or moderate in eight different glioblastoma cell lines compared to Hodgkin's lymphoma cells, known to harbor aberrant constitutive NF-κB activity. Specific inhibition of NF-κB by overexpression of inhibitor of κB (IκB)α superrepressor did not enhance spontaneous apoptosis of glioblastoma cells. Also, overexpression of IκBα superrepressor had no significant impact on apoptosis induced by two prototypic classes of apoptotic stimuli, that is, chemotherapeutic drugs or death-inducing ligands such as TNF-related apoptosis inducing ligand (TRAIL), which are known to trigger NF-κB activation as part of a cellular stress response. Similarly, inhibition of NF-κB by the proteasome inhibitor MG132 did not increase doxorubicin (Doxo)-induced apoptosis of glioblastoma cells, although it prevented DNA binding of NF-κB complexes in response to Doxo. Interestingly, proteasome inhibition significantly sensitized glioblastoma cells for TRAIL-induced apoptosis. These findings indicate that the characteristic antiapoptotic function of NF-κB reported for many cancers is not a primary feature of glioblastoma and thus, specific NF-κB inhibition may not be effective for chemosensitization of glioblastoma. Instead, proteasome inhibitors, which enhanced TRAIL-induced apoptosis in an NF-κB-independent manner, may open new perspectives to increase the efficacy of TRAIL-based regimens in glioblastoma, which warrants further investigation. © 2007 Nature Publishing Group All rights reserved.

Item Type: Article
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculty of Science and Health > Biological Sciences, School of
Depositing User: Jim Jamieson
Date Deposited: 29 Jun 2017 10:02
Last Modified: 17 Aug 2017 17:55
URI: http://repository.essex.ac.uk/id/eprint/8327

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