Type

Other / n/a

Authors

Brona M Murphy
Jochen HM Prehn
A G Letai
D Kögel
Kah P Loh
Sarah Schimansky
Seán M Kilbride
Janis Noonan
Birgit Weyhenmeyer
Áine C Murphy

Subjects

Biochemistry

Topics
apoptosis inducing factor trail glioblastoma r roscovitine physics mc1 1 physiology tumour necrosis factor

Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis. (2014)

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 -> Physiology and Medical Physics Articles
Ireland -> Royal College of Surgeons in Ireland -> Department of Physiology and Medical Physics

Full list of authors on original publication

Brona M Murphy, Jochen HM Prehn, A G Letai, D Kögel, Kah P Loh, Sarah Schimansky, Seán M Kilbride, Janis Noonan, Birgit Weyhenmeyer, Áine 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