Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance
Permanent lenke
https://hdl.handle.net/10037/8510Dato
2015-11-25Type
Journal articleTidsskriftartikkel
Peer reviewed
Forfatter
Wickström, Malin; Dyberg, Cecilia; Milosevic, Jelena; Einvik, Christer; Calero, Raul; Sveinbjørnsson, Baldur; Sandén, Emma; Darabi, Anna; Siesjö, Peter; Kool, Marcel; Kogner, Per; Baryawno, Ninib; Johnsen, John IngeSammendrag
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.
Beskrivelse
Published version also available at http://dx.doi.org/10.1038/ncomms9904