Cited by 1,048Metabolism, Diabetes, and CancerPI3K/AKT/mTOR signaling in cancerCancer, Hypoxia, and Metabolism

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Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells

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Zakikhani, Mahvash, Dowling, Ryan, Fantus, I. George, Sonenberg, Nahum, Pollak, Michael·2006·Cancer Research

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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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Authors: Zakikhani, M., Dowling, R., Fantus, I. G., Sonenberg, N., & Pollak, M.
Affiliations: 1Oncology and Departments of
McGill University (CA)
Mount Sinai Hospital (CA)
ORCID: Dowling, Ryan
Sonenberg, Nahum
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2006-11-01
Volume: 66
Issue: 21
Pages: 10269-10273
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-06-1500
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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Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells

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