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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
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
cell viability assay
controlled study
disease resistance
down regulation
enzyme activation
gene silencing
glioma cell
human cell
human cell culture
priority journal
protein expression
protein targeting
Brain Neoplasms
drug effects
drug potentiation
drug resistance
tumor cell line
Antineoplastic Agents
Brain Neoplasms
Caspase 3
Caspase 8
Cell Line, Tumor
Drug Resistance, Neoplasm
Drug Synergism
Enzyme Activation
Gene Silencing
Myeloid Cell Leukemia Sequence 1 Protein
Proto-Oncogene Proteins c-bcl-2
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.
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
ISSN: 1360-8185
DOI: 10.1007/s10495-013-0935-2
Rights: Attribution 4.0 International
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