Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis
Murphy, Á. C.
Kilbride, S. M.
Loh, K. P.
Letai, A. G.
Prehn, J. H. M.
Murphy, B. M.Note: Order does not necessarily reflect citation order of authors.
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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.
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.
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