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Metformin suppresses azoxymethane‐induced colorectal aberrant crypt foci by activating AMP‐activated protein kinase
Author(s) -
Hosono Kunihiro,
Endo Hiroki,
Takahashi Hirokazu,
Sugiyama Michiko,
Uchiyama Takashi,
Suzuki Kaori,
Nozaki Yuichi,
Yoneda Kyoko,
Fujita Koji,
Yoneda Masato,
Inamori Masahiko,
Tomatsu Akiko,
Chihara Takeshi,
Shimpo Kan,
Nakagama Hitoshi,
Nakajima Atsushi
Publication year - 2010
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20637
Subject(s) - metformin , azoxymethane , ampk , pi3k/akt/mtor pathway , aberrant crypt foci , biology , endocrinology , medicine , protein kinase a , proliferating cell nuclear antigen , amp activated protein kinase , cell growth , carcinogenesis , cancer research , kinase , signal transduction , insulin , colorectal cancer , microbiology and biotechnology , biochemistry , cancer , colonic disease
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. © 2010 Wiley‐Liss, Inc.