Date of Award

Spring 2018

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Professor Markus Rehm

Second Supervisor

Dr Brona Murphy

Funder/Sponsor

Irish Research Council

Keywords

TRAIL, IAP Antagonist, TL32711, Glioblastoma

Abstract

Glioblastoma (GBM) is the most aggressive form of primary brain tumour with no effective approved treatment being available. Here, we, therefore, studied the responsiveness of GBM cell lines to combination treatments with death ligand TRAIL and IAP antagonist TL32711 (Birinapant). Responses were highly heterogeneous, with synergistic death responses as well as treatment resistance being observed. Compared to resistant cell lines, all TRAIL+TL32711-responsive cell lines expressed significantly higher amounts of procaspase-8 (PC8), and Bid. The expression of other TRAIL pathway components or IAP proteins did not differ notably between responders and non-responders. The direct interplay of PC8 and Bid forms a pro-apoptotic axis that efficiently induced apoptosis, the only cell death modality observed, in responder cell lines. We, therefore, hypothesised that improving the efficiency of caspase-8 activation or sensitising mitochondria to Bid could convert non-responder GBM cell lines to responders, despite their low basal PC8/Bid expression. Indeed, both siRNA-based cFLIP depletion and in particular Bcl-2 antagonism by ABT-199, allowed us to eliminate otherwise TRAIL+TL32711-resistant cell lines by apoptosis. Our study, therefore, shows that a high PC8 and Bid signature predicts synergistic TRAIL+TL32711-induced apoptosis in GBM and outlines potent interventions, both upstream and downstream of the PC8 and Bid interplay, to sensitize resistant GBM cells characterised by expression of these two proteins.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

4.81 MB

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2018.

Share

COinS