title: Inhibition of the GTPase Rac1 mediates the antimigratory effects of metformin in prostate cancer cells.
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.
authors.affiliation: INSERM, C3M, U1065, Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France. Univ. Nice Sophia Antipolis, C3M, U1065, Nice, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Dirat
authors.affiliation: CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France. Université de Toulouse, UPS, IPBS, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ader
authors.affiliation: CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France. Université de Toulouse, UPS, IPBS, Toulouse, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Golzio
authors.affiliation: INSERM, C3M, U1065, Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France. Univ. Nice Sophia Antipolis, C3M, U1065, Nice, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Massa
authors.affiliation: 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.
authors.forename: Amel
authors.initials: A
authors.lastname: Mettouchi
authors.affiliation: INSERM, C3M, U1065, Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France. Univ. Nice Sophia Antipolis, C3M, U1065, Nice, France.
authors.forename: Kathiane
authors.initials: K
authors.lastname: Laurent
authors.affiliation: University of Nice Sophia Antipolis, EA6302, Flow Cytometry Facility, Hôpital l'Archet 1, Nice, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Larbret
authors.affiliation: 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.
authors.forename: Bernard
authors.initials: B
authors.lastname: Malavaud
authors.affiliation: INSERM, C3M, U1065, Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France. Univ. Nice Sophia Antipolis, C3M, U1065, Nice, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Cormont
authors.affiliation: 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.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lemichez
authors.affiliation: CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France. Université de Toulouse, UPS, IPBS, Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cuvillier
authors.affiliation: INSERM, C3M, U1065, Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France. Univ. Nice Sophia Antipolis, C3M, U1065, Nice, France.
authors.forename: Jean François
authors.initials: JF
authors.lastname: Tanti
authors.affiliation: 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.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bost
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D020662:Guanine Nucleotide Exchange Factors; C453280:PREX1 protein, human; D008687:Metformin; D000242:Cyclic AMP; D020830:rac1 GTP-Binding Protein