Advanced

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

Wickström, Malin; Dyberg, Cecilia; Milosevic, Jelena; Einvik, Christer; Calero, Raul; Sveinbjörnsson, Baldur; Sandén, Emma LU ; Darabi, Anna LU ; Siesjö, Peter LU and Kool, Marcel, et al. (2015) In Nature Communications 6.
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
6
publisher
Nature Publishing Group
external identifiers
  • pmid:26603103
  • wos:000366378900006
  • scopus:84948686634
ISSN
2041-1723
DOI
10.1038/ncomms9904
language
English
LU publication?
yes
id
7ece7ffd-f3f5-4953-93fd-69eaa616c190 (old id 8234632)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26603103?dopt=Abstract
date added to LUP
2015-12-02 21:20:33
date last changed
2017-11-12 03:44:09
@article{7ece7ffd-f3f5-4953-93fd-69eaa616c190,
  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.},
  articleno    = {8904},
  author       = {Wickström, Malin and Dyberg, Cecilia and Milosevic, Jelena and Einvik, Christer and Calero, Raul and Sveinbjörnsson, Baldur and Sandén, Emma and Darabi, Anna and Siesjö, Peter and Kool, Marcel and Kogner, Per and Baryawno, Ninib and Johnsen, John Inge},
  issn         = {2041-1723},
  language     = {eng},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance.},
  url          = {http://dx.doi.org/10.1038/ncomms9904},
  volume       = {6},
  year         = {2015},
}