Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance

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Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance

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Title: Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance
Author: Wickström, Malin; Dyberg, Cecilia; Milosevic, Jelena; Einvik, Christer; Calero, Raul; Sveinbjörnsson, Baldur; Sandén, Emma; Darabi, Anna; Siesjö, Peter; Kool, Marcel; Kogner, Per; Baryawno, Ninib; Johnsen, John Inge

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Citation: Wickström, M., C. Dyberg, J. Milosevic, C. Einvik, R. Calero, B. Sveinbjörnsson, E. Sandén, et al. 2015. “Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance.” Nature Communications 6 (1): 8904. doi:10.1038/ncomms9904. http://dx.doi.org/10.1038/ncomms9904.
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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.
Published Version: doi:10.1038/ncomms9904
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674781/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:23993616
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