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Metformin inhibits the development and metastasis of colorectal cancer

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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.

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Data availability

The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank K. Koishikawa for technical supports and mouse handling: H. Nikki March, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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The authors have received no specific grants from any funding.

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Authors and Affiliations

  1. Department of Surgery, Keio University School of Medicine, 35 Shinanomachi Shinjyuku-Ku, Tokyo, 160-8582, Japan

    Kiyoaki Sugiura, Koji Okabayashi, Ryo Seishima, Kohei Shigeta, Masashi Tsuruta & Yuko Kitagawa

  2. Surgery, Ashikaga Red Cross Hospital, Tochigi, Japan

    Kiyoaki Sugiura

  3. Department of Hepato-Biliary-Pancreatic & Gastrointestinal Surgery, and Welfare, School of Medicine, International University of Health, Chiba, Japan

    Takashi Ishida & Masashi Tsuruta

  4. Department of Surgery, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan

    Hirotoshi Hasegawa

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  1. Kiyoaki Sugiura
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Kiyoaki Sugiura. The first draft of the manuscript was written by Kiyoaki Sugiura. Koji Okabayashi revised previous version of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Koji Okabayashi.

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Approval was granted by the Animal Experiments Committee of Keio University. (No. 15025-(0)).

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Sugiura, K., Okabayashi, K., Seishima, R. et al. Metformin inhibits the development and metastasis of colorectal cancer. Med Oncol 39, 136 (2022). https://doi.org/10.1007/s12032-022-01722-y

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