Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells
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Abstract
Recent population studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers. This drug is widely used in the treatment of type 2 diabetes, where it is often referred to as an "insulin sensitizer" because it not only lowers blood glucose but also reduces the hyperinsulinemia associated with insulin resistance. As insulin and insulin-like growth factors stimulate proliferation of many normal and transformed cell types, agents that facilitate signaling through these receptors would be expected to enhance proliferation. We show here that metformin acts as a growth inhibitor rather than an insulin sensitizer for epithelial cells. Breast cancer cells can be protected against metformin-induced growth inhibition by small interfering RNA against AMP kinase. This shows that AMP kinase pathway activation by metformin, recently shown to be necessary for metformin inhibition of gluconeogenesis in hepatocytes, is also involved in metformin-induced growth inhibition of epithelial cells. The growth inhibition was associated with decreased mammalian target of rapamycin and S6 kinase activation and a general decrease in mRNA translation. These results provide evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent population studies and justify further work to explore potential roles for activators of AMP kinase in cancer prevention and treatment.
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Some proposed anti-cancer mechanisms of metformin may be through inhibition of cell growth, IGF-1 signaling, mTOR pathway, reduction of HER-2 expression, inhibition of angiogenesis and inflammation, induction of apoptosis and p53 activation, cell cycle arrest, and enhancement of CD8 T cell memory.
“Some of these mechanisms may be through inhibition of cell growth [148], IGF-1 signaling [149], inhibition of the mTOR pathway [150], reduction of human epidermal growth factor receptor type 2 (HER-2) expression (a major driver of proliferation in breast cancer) [151], inhibition of angiogenesis and inflammation [152], induction of apoptosis and protein 53 (p53) activation [153], cell cycle arrest”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [150]
Animal experiments have elucidated the mechanisms underlying these epidemiological findings, i.e., interference with glucose, protein, and lipid metabolism of the neoplastic cells.
“and interference with glucose(266), protein(267, 268), and lipid(269) metabolism of the neoplastic cells.”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [268]
In laboratory studies, metformin inhibits cell proliferation, reduces colony formation, and causes partial cell cycle arrest in cancer cell lines.
“In laboratory studies, metformin has been shown to inhibit cell proliferation, reduce colony formation, and cause partial cell cycle arrest in cancer cell lines (81–83).”
From Diabetes and Cancer (2010) · cites this paper as [81]
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- Authors
- Zakikhani, M., Dowling, R., Fantus, I. G., Sonenberg, N., & Pollak, M.
- Affiliations
- 1Oncology and Departments of
- McGill University (CA)
- Mount Sinai Hospital (CA)
- Venue
- Cancer Research
- Published
- 2006-11-01
- Volume
- 66
- Issue
- 21
- Pages
- 10269-10273
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2078190084
- Cited by
- 1,048
- References
- 20
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 24 · 2023: 29 · 2022: 28 · 2021: 54 · 2020: 47 · 2019: 62 · 2018: 55 · 2017: 70 · 2016: 70 · 2015: 80 · 2014: 93 · 2013: 86 · 2012: 85
- FWCI
- 12.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- eScholarship@McGill (McGill) (submittedVersion)
- Funders
- Canadian Breast Cancer Research Alliance
- Terry Fox Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- metformin, AMP kinase, breast cancer, cell growth inhibition, antineoplastic effects, mTOR, S6 kinase, mRNA translation, insulin resistance, insulin-like growth factor, epithelial cells, cancer prevention
- MeSH terms
- Adenylate Kinase, Antineoplastic Agents, Breast Neoplasms, Female, Humans, Insulin, Metformin, Protein Biosynthesis, Gene Expression Regulation, Enzymologic, RNA, Small Interfering, Cell Line, Tumor, Cell Proliferation
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