Peer Reviewed

1

Document Type

Article

Publication Date

1-4-2014

Keywords

Glioblastoma, TRAIL, R-roscovitine, Mc1-1

Funder/Sponsor

Health Research Board (RP/2008/69 and HRA_POR/ 2012/88) and the RCSI Research Committee (GR 08-0155) to BMM. BMM is a Science Foundation Ireland Stokes Lecturer (07/SK/B1243a). Deutsche Krebshilfe (grant 108795) to DK. SK was supported by a Science Foundation Ireland Short Term Travel Fellowship (08/IN.1/B1949-STTF 11).

Comments

This article is also available at http://link.springer.com/article/10.1007%2Fs10495-013-0935-2

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.

Disciplines

Physics | Physiology

Citation

Murphy AC, Weyhenmeyer B, Noonan J, Kilbride SM, Schimansky S, Loh KP, Kogel D, Letai AG, Prehn JHM, Murphy B. Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis. Apoptosis. 2014;19(4);629-642.

PubMed ID

24213561

DOI Link

10.1007/s10495-013-0935-2

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