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

Kunihiro Hosono, Hiroki Endo, Hirokazu Takahashi, Michiko Sugiyama, Takashi Uchiyama, Kaori Suzuki, Yuichi Nozaki, Kyoko Yoneda, Koji Fujita, Masato Yoneda, Masahiko Inamori, Akiko Tomatsu, Takeshi Chihara, Kan Shimpo, Hitoshi Nakagama, Atsushi Nakajima

Research output: Contribution to journalArticle

132 Citations (Scopus)

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, 10mg/kg) and then treated with or without metformin (250mg/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.

Original languageEnglish
Pages (from-to)662-671
Number of pages10
JournalMolecular Carcinogenesis
Volume49
Issue number7
DOIs
Publication statusPublished - 01-07-2010

Fingerprint

Aberrant Crypt Foci
Azoxymethane
AMP-Activated Protein Kinases
Metformin
Sirolimus
Proliferating Cell Nuclear Antigen
Bromodeoxyuridine
Adenosine Monophosphate
Polyps
Protein Kinases
Ribosomal Protein S6 Kinases
S 6
Chemoprevention
Hypoglycemic Agents
Carcinogens
Insulin Resistance
Colorectal Neoplasms
Diabetes Mellitus
Colon
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

Cite this

Hosono, K., Endo, H., Takahashi, H., Sugiyama, M., Uchiyama, T., Suzuki, K., ... Nakajima, A. (2010). Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase. Molecular Carcinogenesis, 49(7), 662-671. https://doi.org/10.1002/mc.20637
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. / Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase. In: Molecular Carcinogenesis. 2010 ; Vol. 49, No. 7. pp. 662-671.
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Hosono, K, Endo, H, Takahashi, H, Sugiyama, M, Uchiyama, T, Suzuki, K, Nozaki, Y, Yoneda, K, Fujita, K, Yoneda, M, Inamori, M, Tomatsu, A, Chihara, T, Shimpo, K, Nakagama, H & Nakajima, A 2010, 'Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase', Molecular Carcinogenesis, vol. 49, no. 7, pp. 662-671. https://doi.org/10.1002/mc.20637

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

In: Molecular Carcinogenesis, Vol. 49, No. 7, 01.07.2010, p. 662-671.

Research output: Contribution to journalArticle

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T1 - Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase

AU - Hosono, Kunihiro

AU - Endo, Hiroki

AU - Takahashi, Hirokazu

AU - Sugiyama, Michiko

AU - Uchiyama, Takashi

AU - Suzuki, Kaori

AU - Nozaki, Yuichi

AU - Yoneda, Kyoko

AU - Fujita, Koji

AU - Yoneda, Masato

AU - Inamori, Masahiko

AU - Tomatsu, Akiko

AU - Chihara, Takeshi

AU - Shimpo, Kan

AU - Nakagama, Hitoshi

AU - Nakajima, Atsushi

PY - 2010/7/1

Y1 - 2010/7/1

N2 - 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, 10mg/kg) and then treated with or without metformin (250mg/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.

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