Journal Article

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

Sveinbjörnsson, Baldur, Siesjö, Peter, Milosevic, Jelena, Wickström, Malin, Kogner, Per, Baryawno, Ninib, Einvik, Christer, Calero, Raul, Darabi, Anna, Kool, Marcel, Sandén, Emma, Dyberg, Cecilia, Johnsen, John Inge

2015

Overview

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. The high expression of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) often confers resistance to chemotherapy in several cancers. In this study, the authors propose the inhibition of the Wnt signalling pathway as an alternative strategy to modulate MGMT expression and sensitize tumours to chemotherapy.

• Publisher: Nature Publishing Group UK,Nature Pub. Group
• Subject: 13 / 13/1 / 13/109 / 13/31 / 13/51 / 14/34 / 631/45/607/1159 / 631/67/1059/2326 / 631/80/86 / 64/60 / Animals / Antineoplastic Agents - pharmacology / Basic Medicine / Benzeneacetamides - pharmacology / beta Catenin - genetics / beta Catenin - metabolism / Brain Neoplasms - drug therapy / Brain Neoplasms - genetics / Camptothecin - analogs & derivatives / Camptothecin - pharmacology / Celecoxib - pharmacology / Cell and Molecular Biology / Cell- och molekylärbiologi / Cisplatin - pharmacology / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Dacarbazine - analogs & derivatives / Dacarbazine - pharmacology / DNA Modification Methylases - genetics / DNA Repair Enzymes - genetics / Doxorubicin - pharmacology / Drug Resistance, Neoplasm - genetics / Flow Cytometry / Gene Expression Profiling / Gene Expression Regulation, Neoplastic - drug effects / Gene Expression Regulation, Neoplastic - genetics / Glioma - drug therapy / Glioma - genetics / Glucose-6-Phosphate Isomerase / Heterocyclic Compounds, 3-Ring - pharmacology / Humanities and Social Sciences / Humans / Immunoblotting / Immunohistochemistry / Medical and Health Sciences / Medicin och hälsovetenskap / Medicinska och farmaceutiska grundvetenskaper / Medulloblastoma - drug therapy / Medulloblastoma - genetics / Mice / multidisciplinary / Neoplasm Transplantation / Neoplasms - drug therapy / Neoplasms - genetics / Neuroblastoma - drug therapy / Neuroblastoma - genetics / Pyrans - pharmacology / Pyrazines - pharmacology / Pyridines - pharmacology / Real-Time Polymerase Chain Reaction / Science / Science (multidisciplinary) / Sulfones - pharmacology / Triazoles - pharmacology / Tumor Suppressor Proteins - genetics / Vincristine - pharmacology / Wnt Proteins - genetics / Wnt Proteins - metabolism / Wnt Signaling Pathway - drug effects / Wnt Signaling Pathway - genetics