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Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis

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-r...

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Autores principales: Murphy, Á. C., Weyhenmeyer, B., Noonan, J., Kilbride, S. M., Schimansky, S., Loh, K. P., Kögel, D., Letai, A. G., Prehn, J. H. M., Murphy, B. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938842/
https://www.ncbi.nlm.nih.gov/pubmed/24213561
http://dx.doi.org/10.1007/s10495-013-0935-2
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author Murphy, Á. C.
Weyhenmeyer, B.
Noonan, J.
Kilbride, S. M.
Schimansky, S.
Loh, K. P.
Kögel, D.
Letai, A. G.
Prehn, J. H. M.
Murphy, B. M.
author_facet Murphy, Á. C.
Weyhenmeyer, B.
Noonan, J.
Kilbride, S. M.
Schimansky, S.
Loh, K. P.
Kögel, D.
Letai, A. G.
Prehn, J. H. M.
Murphy, B. M.
author_sort Murphy, Á. C.
collection PubMed
description 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.
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spelling pubmed-39388422014-03-06 Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis Murphy, Á. C. Weyhenmeyer, B. Noonan, J. Kilbride, S. M. Schimansky, S. Loh, K. P. Kögel, D. Letai, A. G. Prehn, J. H. M. Murphy, B. M. Apoptosis Original Paper 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. Springer US 2013-11-09 2014 /pmc/articles/PMC3938842/ /pubmed/24213561 http://dx.doi.org/10.1007/s10495-013-0935-2 Text en © The Author(s) 2013 https://creativecommons.org/licenses/by/2.0/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Original Paper
Murphy, Á. C.
Weyhenmeyer, B.
Noonan, J.
Kilbride, S. M.
Schimansky, S.
Loh, K. P.
Kögel, D.
Letai, A. G.
Prehn, J. H. M.
Murphy, B. M.
Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis
title Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis
title_full Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis
title_fullStr Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis
title_full_unstemmed Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis
title_short Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis
title_sort modulation of mcl-1 sensitizes glioblastoma to trail-induced apoptosis
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938842/
https://www.ncbi.nlm.nih.gov/pubmed/24213561
http://dx.doi.org/10.1007/s10495-013-0935-2
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