title: Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance.
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.
authors.affiliation: Department of Women's and Children's Health, Childhood Cancer Research Unit, Karolinska Institutet, Stockholm S-17176, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Wickström
authors.affiliation: Department of Women's and Children's Health, Childhood Cancer Research Unit, Karolinska Institutet, Stockholm S-17176, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Dyberg
authors.affiliation: Department of Women's and Children's Health, Childhood Cancer Research Unit, Karolinska Institutet, Stockholm S-17176, Sweden.
authors.forename: Jelena
authors.initials: J
authors.lastname: Milosevic
authors.affiliation: Department of Pediatrics, University Hospital of North Norway, Tromsø N-9038, Norway.
authors.forename: Christer
authors.initials: C
authors.lastname: Einvik
authors.affiliation: Department of Women's and Children's Health, Childhood Cancer Research Unit, Karolinska Institutet, Stockholm S-17176, Sweden.
authors.forename: Raul
authors.identifier: http://orcid.org/0000-0003-1525-1921
authors.initials: R
authors.lastname: Calero
authors.affiliation: Department of Women's and Children's Health, Childhood Cancer Research Unit, Karolinska Institutet, Stockholm S-17176, Sweden.|Department of Medical Biology, University of Tromsø, Tromsø N-9037, Norway.
authors.forename: Baldur
authors.initials: B
authors.lastname: Sveinbjörnsson
authors.affiliation: Department of Clinical Sciences Lund, Glioma Immunotherapy Group, Division of Neurosurgery, Lund University, Lund S-22185, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Sandén
authors.affiliation: Department of Clinical Sciences Lund, Glioma Immunotherapy Group, Division of Neurosurgery, Lund University, Lund S-22185, Sweden.
authors.forename: Anna
authors.identifier: http://orcid.org/0000-0003-4326-8149
authors.initials: A
authors.lastname: Darabi
authors.affiliation: Department of Clinical Sciences Lund, Glioma Immunotherapy Group, Division of Neurosurgery, Lund University, Lund S-22185, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Siesjö
authors.affiliation: Division of Pediatric Neuro-Oncology, German Cancer Research Center, DKFZ, Heidelberg 69120, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.affiliation: Department of Women's and Children's Health, Childhood Cancer Research Unit, Karolinska Institutet, Stockholm S-17176, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Kogner
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.|Center for Regenerative Medicine and the Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors.forename: Ninib
authors.initials: N
authors.lastname: Baryawno
authors.affiliation: Department of Women's and Children's Health, Childhood Cancer Research Unit, Karolinska Institutet, Stockholm S-17176, Sweden.
authors.forename: John Inge
authors.initials: JI
authors.lastname: Johnsen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D044482:Benzeneacetamides / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D000068579:Celecoxib / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D005910:Glioma / Q000188:drug therapy / Q000235:genetics; D005956:Glucose-6-Phosphate Isomerase; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D000077146:Irinotecan; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics; D011714:Pyrans / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D013450:Sulfones / Q000494:pharmacology; D000077204:Temozolomide; D014230:Triazoles / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014750:Vincristine / Q000494:pharmacology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D044482:Benzeneacetamides; D002166:Camptothecin; D000068579:Celecoxib; D002945:Cisplatin; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D003606:Dacarbazine; D004317:Doxorubicin; D005956:Glucose-6-Phosphate Isomerase; D006575:Heterocyclic Compounds, 3-Ring; D000077146:Irinotecan; D011714:Pyrans; D011719:Pyrazines; D011725:Pyridines; D013450:Sulfones; D000077204:Temozolomide; D014230:Triazoles; D025521:Tumor Suppressor Proteins; D014750:Vincristine; D051153:Wnt Proteins; D051176:beta Catenin; C579131:2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl)acetamide; C582305:G007-LK; C544261:XAV939; C010327:salinomycin; D000095662:Polyether Polyketides; C515491:MGMT protein, human; C586458:LGK974