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dc.contributor.authorMurphy, Á. C.en_US
dc.contributor.authorWeyhenmeyer, B.en_US
dc.contributor.authorNoonan, J.en_US
dc.contributor.authorKilbride, S. M.en_US
dc.contributor.authorSchimansky, S.en_US
dc.contributor.authorLoh, K. P.en_US
dc.contributor.authorKögel, D.en_US
dc.contributor.authorLetai, A. G.en_US
dc.contributor.authorPrehn, J. H. M.en_US
dc.contributor.authorMurphy, B. M.en_US
dc.date.accessioned2014-04-11T14:13:10Z
dc.date.issued2013en_US
dc.identifier.citationMurphy, Á. C., B. Weyhenmeyer, J. Noonan, S. M. Kilbride, S. Schimansky, K. P. Loh, D. Kögel, A. G. Letai, J. H. M. Prehn, and B. M. Murphy. 2013. “Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis.” Apoptosis 19 (1): 629-642. doi:10.1007/s10495-013-0935-2. http://dx.doi.org/10.1007/s10495-013-0935-2.en
dc.identifier.issn1360-8185en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:12064545
dc.description.abstractGlioblastoma (GBM) is the most aggressive form of primary brain tumour, with dismal patient outcome. Treatment failure is associated with intrinsic or acquired apoptosis resistance and the presence of a highly tumourigenic subpopulation of cancer cells called GBM stem cells. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising novel therapy for some treatment-resistant tumours but unfortunately GBM can be completely resistant to TRAIL monotherapy. In this study, we identified Mcl-1, an anti-apoptotic Bcl-2 family member, as a critical player involved in determining the sensitivity of GBM to TRAIL-induced apoptosis. Effective targeting of Mcl-1 in TRAIL resistant GBM cells, either by gene silencing technology or by treatment with R-roscovitine, a cyclin-dependent kinase inhibitor that targets Mcl-1, was demonstrated to augment sensitivity to TRAIL, both within GBM cells grown as monolayers and in a 3D tumour model. Finally, we highlight that two separate pathways are activated during the apoptotic death of GBM cells treated with a combination of TRAIL and R-roscovitine, one which leads to caspase-8 and caspase-3 activation and a second pathway, involving a Mcl-1:Noxa axis. In conclusion, our study demonstrates that R-roscovitine in combination with TRAIL presents a promising novel strategy to trigger cell death pathways in glioblastoma. Electronic supplementary material The online version of this article (doi:10.1007/s10495-013-0935-2) contains supplementary material, which is available to authorized users.en
dc.language.isoen_USen
dc.publisherSpringer USen
dc.relation.isversionofdoi:10.1007/s10495-013-0935-2en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938842/pdf/en
dash.licenseLAAen_US
dc.subjectGlioblastomaen
dc.subjectTRAILen
dc.subjectR-roscovitineen
dc.subjectMcl-1en
dc.titleModulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosisen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalApoptosisen
dc.date.available2014-04-11T14:13:10Z
dc.identifier.doi10.1007/s10495-013-0935-2*
dash.authorsorderedfalse


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