Volume 2 Supplement 1

Metabolism, Diet and Disease 2014: Cancer and metabolism

Open Access

Metformin targets the GTPase Rac1 to inhibit prostate cancer cell migration

  • Béatrice Dirat1, 2,
  • Isabelle Ader2,
  • Muriel Golzio2,
  • Amel Mettouchi1, 2,
  • Kathiane Laurent1, 2,
  • Frédéric Larbret2,
  • Bernard Malavaud3, 2,
  • Mireille Cormont1, 2,
  • Emmanuel Lemichez1, 2,
  • Jean François Tanti1, 2 and
  • Frédéric Bost1, 2
Cancer & Metabolism20142(Suppl 1):O24

https://doi.org/10.1186/2049-3002-2-S1-O24

Published: 28 May 2014

Background

The anti-diabetic drug metformin has been shown to affect cancer cell metabolism [1, 2] and to display anti-tumoral properties in numerous cancers [3, 4], however, its role in the formation of metastases remains poorly documented. Cell migration is a critical step in the progression of prostate cancer to the metastatic state, the lethal form of the disease.

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.

Conclusion

Our results establish a novel mechanism of action for metformin through Rac1 and highlight its potential anti-metastatic properties in prostate cancer.

Declarations

Acknowledgement

This research was supported by The French National Institute for Cancer (INCa) and The foundation ARC.

Authors’ Affiliations

(1)
INSERM U1065, C3M
(2)
CNRS U5089 IPBS
(3)
Rangeuil Hospital

References

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Copyright

© Dirat et al; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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