SFEBES2018 Poster Presentations Adrenal and steroids (38 abstracts)
Glucocorticoids promote DNA repair to reduce efficacy of radiotherapy in Glioblastoma
Kathryn Mc Ginnis 1 , Syed Murtuza Baker 2 , Andrew Berry 2 , Thomas Ward 1 , Magnus Rattray 2 , David Ray 2 , Graham Cook 1 , Jacquelyn Bond 1 & Laura Matthews 1
1University of Leeds, Leeds, UK; 2University of Manchester, Manchester, UK.
Glioblastoma (GBM) is a highly aggressive form of brain cancer with a median survival time of 12–15 months from diagnosis. Standard therapies utilise a combination of radiotherapy, chemotherapy, and surgery. Patients also receive high doses of the potent anti-inflammatory glucocorticoid (Gc), Dexamethasone (Dex).Recent studies show that patients receiving the highest dose of Dex also have reduced survival time. Defining pathways under Gc control relevant to GBM is necessary to understand how Gc may affect the efficacy of standard cancer therapies. We have used genome-wide transcriptional profiling (RNA-seq) of GBM cells treated with a vehicle control, two doses of hydrocortisone (HC, corresponding to minimum and maximum endogenous levels), or an equivalent therapeutic dose of Dex. We identify Gc dependent regulation of 307 genes (>1.5 fold change, FDR <0.05). Of these, 37 genes are regulated by all three treatments, 72 genes are regulated by high HC and Dex, and 140 genes are regulated by Dex alone. Gene ontology analysis across all Gc-regulated transcripts predicts changes in the activity of IL-6, NFkB and AP-1 pathways, consistent with anti-inflammatory effects. Gc were also predicted to affect cell cycle and DNA repair pathways, largely through control of p53 effector proteins. This is particularly relevant in the context of GBM treatment, as radiotherapy and chemotherapy both rely on the induction of DNA damage to induce GBM cell death. We demonstrate that Gc treatment reduces levels of DNA damage (COMET assay), thereby increasing survival (MTT assay) of GBM cells following irradiation. This Gc induced radioresistance occurs in cells which lack functional DNA-PK, suggesting a DNA-PK independent mechanism. Our study now reveals novel Gc actions which affect genome stability and treatment efficacy in GBM.
Volume 59
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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