Date of Award

2011

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Brona Murphy

Keywords

Glioblastoma, Therapy

Abstract

GBM (Glioblastoma multiforme) is the most aggressive form of primary brain tumour, with dismal patient outcome. Treatment failure is often associated with intrinsic or acquired apoptosis resistance and aberrant signalling of survival pathways.

In this work, we analysed apoptosis resistance in gliomas in order to improve treatment predictions and the accuracy of prognosis for patients suffering from GBM. We successfully correlated protein expression profiles of 21 pro- and anti-apoptotic proteins in glioma cell lines with chemotherapeutic sensitivity to mono-therapy with TMZ or TRAIL and to combined therapy with TMZ and TRAIL in these cell lines, using single protein analysis, the multivariate principal component analysis and the computational model APOPTO CELL. We found that sensitivity to TMZ was sufficiently predicted by analysing the components involved in the late steps of apoptosis after the release of cytochrome c. Sensitivity to TRAIL or a combination of TMZ and TRAIL was best explained by the analysis of all 21 apoptotic proteins, which are involved in an interactive network in extrinsic and intrinsic apoptotic pathways. Our results also revealed a high predictive value of the anti-apoptotic proteins XIAP and B c1-x l and the pro-apoptotic protein procaspase-3 in the determination of apoptosis resistance in glioblastomas.

The BH3-only protein Bim was extensively downregulated in most glioma cell lines and all GBM patient samples. Additionally, a glioma cell line with high intrinsic expression of Bim showed further upregulation of Bim levels during treatment, which was also associated with an enhanced cell death following combination therapy with TMZ and TRAIL. Our results suggest that Bim is transcriptionally regulated during TMZ- and TRAIL-induced apoptosis by the transcription factor Fox03a, which itself is posttranscriptionally controlled by phosphorylation mediated through the Ras/ RAF/ ERK1/2 survival signalling pathway. Thus, we hypothesise that the repression of Bim activity is a pivotal step during tumourigenesis, which is conferred by both the dysregulation of the apoptotic pathway and aberrant survival signalling.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

File Size

10.6 MB

Comments

Submitted for the Award of Doctor of Philosophy (PhD) to the Royal College of Surgeons, 2011.

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