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Cited by 861Metabolism, Diabetes, and CancerCancer, Hypoxia, and MetabolismPI3K/AKT/mTOR signaling in cancer

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

Sahra, I Ben, Laurent, K, Loubat, A, Giorgetti-Peraldi, S, Colosetti, P, Auberger, P, Tanti, J F, Le Marchand-Brustel, Y +1 more·2008·Oncogene
DOI 10.1038/sj.onc.1211024
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Abstract

Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G(0)/G(1). This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27(kip) protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.

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Crossref · 10.1038/sj.onc.1211024

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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 [148]

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Authors
Sahra, I. B., Laurent, K., Loubat, A., Giorgetti-Peraldi, S., Colosetti, P., Auberger, P., Tanti, J. F., Le Marchand-Brustel, Y., & Bost, F.
Affiliations
Inserm (FR)
Corresponding author
Bost, F
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2008-01-21
Volume
27
Issue
25
Pages
3576-3586
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/sj.onc.1211024
OpenAlex
W2093664485
Cited by
861
References
41
Citations by year
2026: 14 · 2025: 14 · 2024: 22 · 2023: 17 · 2022: 37 · 2021: 40 · 2020: 37 · 2019: 48 · 2018: 46 · 2017: 70 · 2016: 67 · 2015: 81 · 2014: 87 · 2013: 72 · 2012: 76
FWCI
18.26
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
metformin, prostate cancer, cyclin D1, anticancer activity, cell cycle arrest, p27, retinoblastoma protein phosphorylation, tumor growth inhibition, xenografts, antidiabetic drugs, chemoprevention
MeSH terms
Antineoplastic Agents, Cell Survival, Humans, Hypoglycemic Agents, Male, Metformin, Multienzyme Complexes, Prostate, Prostatic Neoplasms, Gene Expression Regulation, Neoplastic, Apoptosis, Protein Serine-Threonine Kinases, Cyclin D1, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p27, AMP-Activated Protein Kinases

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