Type

Journal Article

Authors

B M Murphy
J H M Prehn
A G Letai
D Kögel
K P Loh
S Schimansky
S M Kilbride
J Noonan
B Weyhenmeyer
Á C Murphy

Subjects

Biochemistry

Topics
drug therapy genetics pathology antineoplastic agents proto oncogene proteins c bcl 2 roscovitine drug resistance neoplasm brain neoplasms pmaip1 protein human pharmacology caspase 3 gene silencing cell line tumor tnf related apoptosis inducing ligand apoptosis caspase 8 glioblastoma enzyme activation myeloid cell leukemia sequence 1 protein mcl1 protein human metabolism drug synergism purines humans drug effects

Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis. (2013)

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.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

B M Murphy, J H M Prehn, A G Letai, D Kögel, K P Loh, S Schimansky, S M Kilbride, J Noonan, B Weyhenmeyer, Á C Murphy

Experts in our system

1
Brona M Murphy
Royal College of Surgeons in Ireland
Total Publications: 14
 
2
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
3
Donat Kögel
Royal College of Surgeons in Ireland
Total Publications: 14
 
4
Janis Noonan
Royal College of Surgeons in Ireland
Total Publications: 6
 
5
Birgit Weyhenmeyer
Royal College of Surgeons in Ireland
Total Publications: 6
 
6
Áine C Murphy
Royal College of Surgeons in Ireland
Total Publications: 8