Journal Article

DKFZ-2017-03807

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance.

Wickström, M. ; Dyberg, C. ; Milosevic, J. ; Einvik, C. ; Calero, R. ; Sveinbjörnsson, B. ; Sandén, E. ; Darabi, A. ; Siesjö, P. ; Kool, M.DKFZ* ; Kogner, P. ; Baryawno, N. ; Johnsen, J. I.

2015
Nature Publishing Group London

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Please use a persistent id in citations: doi:10.1038/ncomms9904

Abstract: The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is commonly overexpressed in cancers and is implicated in the development of chemoresistance. The use of drugs inhibiting MGMT has been hindered by their haematologic toxicity and inefficiency. As a different strategy to inhibit MGMT we investigated cellular regulators of MGMT expression in multiple cancers. Here we show a significant correlation between Wnt signalling and MGMT expression in cancers with different origin and confirm the findings by bioinformatic analysis and immunofluorescence. We demonstrate Wnt-dependent MGMT gene expression and cellular co-localization between active β-catenin and MGMT. Pharmacological or genetic inhibition of Wnt activity downregulates MGMT expression and restores chemosensitivity of DNA-alkylating drugs in mouse models. These findings have potential therapeutic implications for chemoresistant cancers, especially of brain tumours where the use of temozolomide is frequently used in treatment.

Keyword(s): 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl)acetamide ; Antineoplastic Agents ; Benzeneacetamides ; G007-LK ; Heterocyclic Compounds, 3-Ring ; LGK974 ; Pyrans ; Pyrazines ; Pyridines ; Sulfones ; Triazoles ; Tumor Suppressor Proteins ; Wnt Proteins ; XAV939 ; beta Catenin ; irinotecan ; Vincristine ; salinomycin ; Dacarbazine ; Doxorubicin ; DNA Modification Methylases ; MGMT protein, human ; Glucose-6-Phosphate Isomerase ; DNA Repair Enzymes ; Celecoxib ; Cisplatin ; Camptothecin ; temozolomide

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Contributing Institute(s):

1. Pädiatrische Neuroonkologie (B062)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2015

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