Metformin inhibits the development and metastasis of colorectal cancer

Kiyoaki Sugiura, Koji Okabayashi, Ryo Seishima, Takashi Ishida, Kohei Shigeta, Masashi Tsuruta, Hirotoshi Hasegawa, Yuko Kitagawa

Research output: Contribution to journalArticlepeer-review

Abstract

Metformin is a commonly used drug for the treatment of diabetes. Accumulating evidence suggests that it exerts anti-cancer effects in many cancers, including colorectal cancer. However, the underlying molecular mechanisms of colorectal cancer metastasis remain unclear. Colorectal cancer cell lines were treated with metformin, and cell proliferation, invasion, and migration were analyzed in vitro. The relationship between metformin and the AMPK–mTOR axis was assessed by Western blot analysis and transfection with small interfering RNA. A colorectal cancer xenograft mouse model was used to observe the effects of metformin on liver metastasis. Immunohistochemical analysis was performed on liver metastatic tumors. In in vitro experiments, metformin significantly inhibited the proliferation, migration, and invasion only in HCT116 and SW837 cells, but not in HCT8 and Lovo cells. Only in HCT116 and SW837, a change in AMPK–mTOR expression was observed in a dose-dependent manner. In colorectal cancer xenograft mice, the liver metastatic rate (10% vs. 50%, p = 0.05) and the number of liver metastatic nodules (0.1/body vs. 1.2/body, p = 0.04) were significantly lower in the metformin group. Tumor proliferation and EMT were decreased and apoptosis was promoted only in metastatic liver tumors of mice treated with metformin. The molecular mechanism of the anti-cancer effects of metformin involves repression of mTOR pathways via AMPK activation. Moreover, the differences in metformin sensitivity depend on the response of the AMPK–mTOR pathway to metformin. Our study provides a theoretical basis for the anti-metastatic treatment of colorectal cancer using metformin.

Original languageEnglish
Article number136
JournalMedical Oncology
Volume39
Issue number9
DOIs
Publication statusPublished - 2022 Sep

Keywords

  • AMP-activated protein kinase
  • Colorectal cancer
  • Mammalian target of rapamycin
  • Metastasis
  • Metformin

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Metformin inhibits the development and metastasis of colorectal cancer'. Together they form a unique fingerprint.

Cite this