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Mol Cancer Ther. 2015 Feb;14(2):586-96. doi: 10.1158/1535-7163.MCT-14-0102. Epub 2014 Dec 19.

Inhibition of the GTPase Rac1 mediates the antimigratory effects of metformin in prostate cancer cells.

Author information

1
INSERM, C3M, U1065, Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France. Univ. Nice Sophia Antipolis, C3M, U1065, Nice, France.
2
CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France. Université de Toulouse, UPS, IPBS, Toulouse, France.
3
Univ. Nice Sophia Antipolis, C3M, U1065, Nice, France. INSERM, C3M, U1065, Equipe Labellisée Ligue Contre le Cancer, Team Microtoxins in Host Pathogens Interactions, Nice, France.
4
University of Nice Sophia Antipolis, EA6302, Flow Cytometry Facility, Hôpital l'Archet 1, Nice, France.
5
CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France. Université de Toulouse, UPS, IPBS, Toulouse, France. Hôpital Rangueil, Service d'Urologie et de Transplantation Rénale, Toulouse, France.
6
INSERM, C3M, U1065, Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France. Univ. Nice Sophia Antipolis, C3M, U1065, Nice, France. bost@unice.fr.

Abstract

Cell migration is a critical step in the progression of prostate cancer to the metastatic state, the lethal form of the disease. The antidiabetic drug metformin has been shown to display antitumoral properties in prostate cancer cell and animal models; however, its role in the formation of metastases remains poorly documented. Here, we show that metformin reduces the formation of metastases to fewer solid organs in an orthotopic metastatic prostate cancer cell model established in nude mice. As predicted, metformin hampers cell motility in PC3 and DU145 prostate cancer cells and triggers a radical reorganization of the cell cytoskeleton. The small GTPase Rac1 is a master regulator of cytoskeleton organization and cell migration. We report that metformin leads to a major inhibition of Rac1 GTPase activity by interfering with some of its multiple upstream signaling pathways, namely P-Rex1 (a Guanine nucleotide exchange factor and activator of Rac1), cAMP, and CXCL12/CXCR4, resulting in decreased migration of prostate cancer cells. Importantly, overexpression of a constitutively active form of Rac1, or P-Rex, as well as the inhibition of the adenylate cyclase, was able to reverse the antimigratory effects of metformin. These results establish a novel mechanism of action for metformin and highlight its potential antimetastatic properties in prostate cancer.

PMID:
25527635
DOI:
10.1158/1535-7163.MCT-14-0102
[Indexed for MEDLINE]
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