Metformin suppresses azoxymethane‐induced colorectal aberrant crypt foci by activating AMP‐activated protein kinase
- 16 June 2010
- journal article
- research article
- Published by Wiley in Molecular Carcinogenesis
- Vol. 49 (7), 662-671
- https://doi.org/10.1002/mc.20637
Abstract
Metformin is widely used for the treatment of diabetes mellitus. Adenosine monophosphate‐activated protein kinase (AMPK) is known to be activated by metformin and to inhibit the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the protein translational machinery and cell proliferation. We examined the effect of metformin on the suppression of colorectal carcinogenesis in chemical carcinogen‐induced models. Seven‐wk‐old BALB/c mice were intraperitoneally (i.p.) injected with azoxymethane (AOM, 10 mg/kg) and then treated with or without metformin (250 mg/kg/d) for 6 wk (for the investigation of aberrant crypt foci [ACF] formation) or 32 wk (for polyp formation). We next investigated colonic epithelial proliferation using bromodeoxyuridine (BrdU) and the proliferating cell nuclear antigen (PCNA) labeling indices. Furthermore, to examine the indirect effect of metformin, the insulin resistance status and the serum lipid levels were assessed. Treatment with metformin significantly reduced ACF formation. The effect of metformin on colon polyp inhibition was relatively modest. No significant difference in body weight or glucose concentration was observed. The BrdU and PCNA indices decreased in mice treated with metformin. A Western blot analysis revealed that the phosphorylated mTOR, S6 kinase, and S6 protein levels in the colonic mucosa decreased significantly in mice treated with metformin. In conclusion, metformin suppresses colonic epithelial proliferation via the inhibition of the mTOR pathway through the activation of AMPK. As metformin is already used daily as an antidiabetic drug, it might be a safe and promising candidate for the chemoprevention of colorectal cancer.This publication has 35 references indexed in Scilit:
- Adiponectin suppresses colorectal carcinogenesis under the high-fat diet conditionGut, 2008
- Cancer Statistics, 2008CA: A Cancer Journal for Clinicians, 2008
- Chemoprevention of Colorectal CancerDigestion, 2007
- Metformin Prevents Alcohol-Induced Liver Injury in the Mouse: Critical Role of Plasminogen Activator Inhibitor-1Gastroenterology, 2006
- Influence of obesity on the risk of developing colon cancerGut, 2006
- DNA polymerase lambda directly binds to proliferating cell nuclear antigen through its confined C‐terminal regionGenes to Cells, 2005
- Role of AMP-activated protein kinase in mechanism of metformin actionJCI Insight, 2001
- Effect of tea on the formation of DNA adducts by azoxymethaneXenobiotica, 1998
- Human aberrant crypt foci with carcinoma in situ from a patient with sporadic colon cancerGastroenterology, 1996
- The labelling index of human and mouse tumours assessed by bromodeoxyuridine staining in vitro and in vivo and flow cytometryCytometry, 1985