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

Oncogene volume 27, pages 3576–3586 (2008)Cite this article

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 G0/G1. This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27kip 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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Abbreviations

AICAR:

5 amino-imidazol-4-carboxamide-1-β-4-ribofuranoside

ACC:

Acetyl Coenzyme-A Carboxylase

AMPK:

AMP-activated protein kinase

pRb:

retinoblastoma protein

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Acknowledgements

This research was supported by INSERM, a grant from Association pour la Recherche sur le Cancer (grant# 3701); Association pour la Recherche sur les tumeurs de la Prostate (ARTP). We thank Dan Mercola for the cells, Gilles Ponzio for scientific discussions, V Corcelle for reading the manuscript. F Bost and JF Tanti are CNRS investigators.

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Authors and Affiliations

  1. INSERM U568, Nice, France

    I Ben Sahra, K Laurent, S Giorgetti-Peraldi, J F Tanti, Y Le Marchand-Brustel & F Bost

  2. Université de Nice Sophia Antipolis, IFR50, Nice, France

    I Ben Sahra, K Laurent, A Loubat, S Giorgetti-Peraldi, P Colosetti, P Auberger, J F Tanti, Y Le Marchand-Brustel & F Bost

  3. INSERM U638, Nice, France

    A Loubat

  4. INSERM U526, Nice, France

    P Colosetti & P Auberger

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  1. I Ben Sahra
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Correspondence to F Bost.

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Sahra, I., Laurent, K., Loubat, A. et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 27, 3576–3586 (2008). https://doi.org/10.1038/sj.onc.1211024

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