Metformin targets the GTPase Rac1 to inhibit prostate cancer cell migration

Béatrice Dirat,Bernard Malavaud,Mireille Cormont,Kathiane Laurent,Jean François Tanti,Isabelle Ader,Amel Mettouchi,Muriel Golzio,Frédéric Larbret,Emmanuel Lemichez,Frédéric Bost

doi:10.1186/2049-3002-2-s1-o24

Abstract

Results We show here that metformin reduces the occurrence of metastases 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 inhibits 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), cyclic AMP and CXCL12/CXCR4, resulting in decreased migration of prostate cancer cells. Importantly, overexpression of a constitutively active form of Rac1 (Rac1-Q61L or Rac1-V12), or P-Rex1 as well as the inhibition of the adenylate cyclase were able to reverse the anti-migratory effects of metformin.

Highlights

The anti-diabetic drug metformin has been shown to affect cancer cell metabolism [1,2] and to display antitumoral properties in numerous cancers [3,4], its role in the formation of metastases remains poorly documented
We show here that metformin reduces the occurrence of metastases in an orthotopic metastatic prostate cancer cell model established in nude mice
We report that metformin inhibits Rac[1] GTPase activity by interfering with some of its multiple upstream signaling pathways, namely P-Rex[1], cyclic AMP and CXCL12/CXCR4, resulting in decreased migration of prostate cancer cells

Summary

Introduction

The anti-diabetic drug metformin has been shown to affect cancer cell metabolism [1,2] and to display antitumoral properties in numerous cancers [3,4], its role in the formation of metastases remains poorly documented. Results We show here that metformin reduces the occurrence of metastases in an orthotopic metastatic prostate cancer cell model established in nude mice.

Results

Conclusion