title: Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis.
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.
authors.affiliation: Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, St. Stephen's Green, Dublin, 2, Ireland.
authors.forename: Á C
authors.initials: ÁC
authors.lastname: Murphy
authors.forename: B
authors.initials: B
authors.lastname: Weyhenmeyer
authors.forename: J
authors.initials: J
authors.lastname: Noonan
authors.forename: S M
authors.initials: SM
authors.lastname: Kilbride
authors.forename: S
authors.initials: S
authors.lastname: Schimansky
authors.forename: K P
authors.initials: KP
authors.lastname: Loh
authors.forename: D
authors.initials: D
authors.lastname: Kögel
authors.forename: A G
authors.initials: AG
authors.lastname: Letai
authors.forename: J H M
authors.initials: JH
authors.lastname: Prehn
authors.forename: B M
authors.initials: BM
authors.lastname: Murphy
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation; D020868:Gene Silencing; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011687:Purines; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077546:Roscovitine; D053148:Caspase 3; D053181:Caspase 8