Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase

Mol Carcinog. 2010 Jul;49(7):662-71. doi: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Anticarcinogenic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Azoxymethane
  • Cell Proliferation / drug effects
  • Colon / cytology
  • Colon / drug effects*
  • Colon / pathology*
  • Colonic Polyps / pathology
  • Colonic Polyps / prevention & control
  • Colorectal Neoplasms / chemically induced
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / prevention & control*
  • Epithelial Cells / drug effects
  • Hypoglycemic Agents / therapeutic use
  • Insulin Resistance
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipids / blood
  • Metformin / therapeutic use*
  • Mice
  • Mice, Inbred BALB C
  • Protein-Serine-Threonine Kinases / metabolism
  • Ribosomal Protein S6 Kinases / metabolism
  • TOR Serine-Threonine Kinases

Substances

  • Anticarcinogenic Agents
  • Hypoglycemic Agents
  • Intracellular Signaling Peptides and Proteins
  • Lipids
  • Metformin
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Protein-Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases
  • AMP-Activated Protein Kinases
  • Azoxymethane