dc.contributor.author | Murphy, Á. C. | en_US |
dc.contributor.author | Weyhenmeyer, B. | en_US |
dc.contributor.author | Noonan, J. | en_US |
dc.contributor.author | Kilbride, S. M. | en_US |
dc.contributor.author | Schimansky, S. | en_US |
dc.contributor.author | Loh, K. P. | en_US |
dc.contributor.author | Kögel, D. | en_US |
dc.contributor.author | Letai, A. G. | en_US |
dc.contributor.author | Prehn, J. H. M. | en_US |
dc.contributor.author | Murphy, B. M. | en_US |
dc.date.accessioned | 2014-04-11T14:13:10Z | |
dc.date.issued | 2013 | en_US |
dc.identifier.citation | Murphy, 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.issn | 1360-8185 | en |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:12064545 | |
dc.description.abstract | Glioblastoma (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.iso | en_US | en |
dc.publisher | Springer US | en |
dc.relation.isversionof | doi:10.1007/s10495-013-0935-2 | en |
dc.relation.hasversion | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938842/pdf/ | en |
dash.license | LAA | en_US |
dc.subject | Glioblastoma | en |
dc.subject | TRAIL | en |
dc.subject | R-roscovitine | en |
dc.subject | Mcl-1 | en |
dc.title | Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis | en |
dc.type | Journal Article | en_US |
dc.description.version | Version of Record | en |
dc.relation.journal | Apoptosis | en |
dc.date.available | 2014-04-11T14:13:10Z | |
dc.identifier.doi | 10.1007/s10495-013-0935-2 | * |
dash.authorsordered | false | |