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:
https://lup.lub.lu.se/record/8234632
- author
- 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. (More)
- Wickström, Malin
; Dyberg, Cecilia
; Milosevic, Jelena
; Einvik, Christer
; Calero, Raul
; Sveinbjörnsson, Baldur
; Sandén, Emma
LU
; Darabi, Anna
LU
; Siesjö, Peter
LU
; Kool, Marcel
; Kogner, Per
; Baryawno, Ninib
and Johnsen, John Inge
(Less)
- organization
- publishing date
- 2015
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 6
- article number
- 8904
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:26603103
- wos:000366378900006
- scopus:84948686634
- pmid:26603103
- 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
- 2016-04-01 14:14:43
- date last changed
- 2022-04-22 02:01:40
@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.}},
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}},
doi = {{10.1038/ncomms9904}},
volume = {{6}},
year = {{2015}},
}