mTOR inhibition and levels of the DNA repair protein MGMT in T98G glioblastoma cells

Smalley, Sarah, Chalmers, Anthony J and Morley, Simon J (2014) mTOR inhibition and levels of the DNA repair protein MGMT in T98G glioblastoma cells. Molecular Cancer, 13 (1). p. 144. ISSN 1476-4598

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Background: Glioblastoma multiforme (GBM), the most common and most aggressive type of primary adult brain
tumour, responds poorly to conventional treatment. Temozolomide (TMZ) chemotherapy remains the most commonly
used treatment, despite a large proportion of tumours displaying TMZ resistance. 60% of GBM tumours have
unmethylated MGMT promoter regions, resulting in an overexpression of the DNA repair protein O6
-methylguanine-DNA methyltransferase (MGMT), which is responsible for tumour resistance to TMZ chemotherapy. Tumours also often exhibit hyperactive PI3-kinase/mTOR signalling, which enables them to resynthesise proteins quickly. Since MGMT is a suicide protein that is degraded upon binding to and repairing TMZ-induced O6-methylguanine adducts, it has been hypothesized that inhibition of translation via the mTOR signalling pathway could generate a tumour-specific reduction in MGMT protein and increase TMZ sensitivity.
Methods: MGMT was monitored at the post-transcriptional, translational and protein levels, to determine what
effect mTOR inhibition was having on MGMT protein expression in vitro.
Results: We show that inhibiting mTOR signalling is indeed associated with acute inhibition of protein synthesis.
Western blots show that despite this, relative to loading control proteins, steady state levels of MGMT protein
increased and MGMT mRNA was retained in heavy polysomes. Whilst TMZ treatment resulted in maintained MGMT
protein levels, concomitant treatment of T98G cells with TMZ and KU0063794 resulted in increased MGMT protein
levels without changes in total mRNA levels.
Conclusions: These in vitro data suggest that, counterintuitively, mTOR inhibition may not be a useful adjunct to TMZ therapy and that more investigation is needed before applying mTOR inhibitors in a clinical setting.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science
R Medicine
Depositing User: Sarah Smalley
Date Deposited: 18 Jun 2014 13:50
Last Modified: 12 Mar 2017 22:07

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