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https://doi.org/10.1007/s10495-013-0935-2
Title: | Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis | Authors: | Murphy, A.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 |
Keywords: | actin caspase 3 caspase 8 FLICE inhibitory protein procaspase 3 procaspase 8 protein Bid protein mcl 1 protein Noxa roscovitine tumor necrosis factor related apoptosis inducing ligand antineoplastic agent caspase 3 caspase 8 MCL1 protein, human myeloid leukemia factor 1 PMAIP1 protein, human protein bcl 2 purine derivative tumor necrosis factor related apoptosis inducing ligand apoptosis article cell viability assay controlled study disease resistance down regulation enzyme activation gene silencing glioblastoma glioma cell human human cell human cell culture neuromodulation priority journal protein expression protein targeting Brain Neoplasms drug effects drug potentiation drug resistance genetics glioblastoma metabolism pathology tumor cell line Antineoplastic Agents Apoptosis Brain Neoplasms Caspase 3 Caspase 8 Cell Line, Tumor Drug Resistance, Neoplasm Drug Synergism Enzyme Activation Gene Silencing Glioblastoma Humans Myeloid Cell Leukemia Sequence 1 Protein Proto-Oncogene Proteins c-bcl-2 Purines TNF-Related Apoptosis-Inducing Ligand |
Issue Date: | 2014 | Publisher: | Kluwer Academic Publishers | Citation: | Murphy, A.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 (2014). Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis. Apoptosis 19 (4) : 629-642. ScholarBank@NUS Repository. https://doi.org/10.1007/s10495-013-0935-2 | Rights: | Attribution 4.0 International | 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. © 2013 The Author(s). | Source Title: | Apoptosis | URI: | https://scholarbank.nus.edu.sg/handle/10635/180765 | ISSN: | 1360-8185 | DOI: | 10.1007/s10495-013-0935-2 | Rights: | Attribution 4.0 International |
Appears in Collections: | Staff Publications Elements |
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