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NaV1.5 sodium channels increase breast cancer cell invadopodial activity by both controlling Src kinase-dependent F-actin polymerization and promoting NHE-1-dependent proton efflux and extracellular matrix digestion

Lucie Brisson1, Virginie Driffort1, Lauriane Benoist1, Mallorie Poet2, Laurent Counillon2, Ester Antelmi3, Rosa Rubino3, Pierre Besson1, Fabien Labbal2, Stépan Chevalier1, Stephan J. Reshkin1, 3, Jacques Goré1 and Sébastien Roger1*
  • 1 UMR inserm 1069 Université François-Rabelais de Tours, France
  • 2 CNRS FRE3472; Université de Nice-Sophia Antipolis, France
  • 3 Department of Biosciences, Biotechnology and Pharmacological Sciences, University of Bari, Italy

Background and aim. The degradation of the extracellular matrix (ECM) by cancer cells is a critical essential step in metastatic progression. NaV1.5 sodium channels are overexpressed in breast tumours and associated with metastatic occurrence. NaV1.5 activity in breast cancer cells promotes ECM degradation through the perimembrane acidification and the subsequent activation of cysteine cathepsins [1,2]. The aim of this study was to identify cellular pathways involved in the NaV1.5-dependent H+ efflux and invasiveness of highly aggressive human MDA-MB-231 breast cancer cells.
Methods. Highly aggressive MDA-MB-231 breast cancer cells express functional NaV1.5 channels. By using cell fractionation and microscopy analyses, we studied the presence of NaV1.5 channels in invadopodia which are key cellular structures for cancer cells invasiveness. In MDA-MB-231-derived cell lines expressing or not NaV1.5 channels (shRNA) we examined the ability of cancer cells to form invadopodia, to invade through an ECM composed of Matrigel™, and to regulate the efflux of protons.
Results. We showed that NaV1.5 was co-localised with NHE-1, and caveolin-1 in MDA-MB-231 breast cancer cells invadopodia, at sites of ECM remodelling. NHE-1, NaV1.5 and caveolin-1 co-immunoprecipitated, which indicated a close association between these proteins. The expression of NaV1.5 was responsible for the allosteric modulation of NHE-1 rendering it more active at intracellular pH range 6.4 to 7, thus potentially extruding more protons in the extracellular space. Furthermore, NaV1.5 increased Src kinase activity and the phosphorylation (Y421) of the actin-nucleation-promoting factor cortactin, controlled F-actin polymerization and the acquisition of an invasive morphology.
Conclusions. This study suggests that NaV1.5 is an important regulator of invadopodia formation (F-actin polymerization) and degradative activity (NHE-1 over-activation resulting in extracellular acidic proteases activation) in breast cancer cells [3].

Acknowledgements

This work was supported by the "Ministère de la Recherche et des Technologies", the Inserm, the "Ligue Nationale Contre le Cancer", by the “Programme Hubert Curien – Galileo” (Campus France) and the "Associazione Italiana per la Ricerca sul Cancro" (AIRC) grant #11348 to SJR. SJR was recipient of a visiting professorship position at the University of Tours in 2013-2014.

References

1. Gillet, L., Roger, S., Besson, P., Lecaille, F., Gore, J., Bougnoux, P., Lalmanach, G. and Le Guennec, J.Y. (2009) Voltage-gated Sodium Channel Activity Promotes Cysteine Cathepsin-dependent Invasiveness and Colony Growth of Human Cancer Cells. J Biol Chem, 284, 8680-91.
2. Brisson, L., Gillet, L., Calaghan, S., Besson, P., Le Guennec, J.Y., Roger, S. and Gore, J. (2011) Na(V)1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H(+) efflux in caveolae. Oncogene, 30, 2070-6.
3. Brisson, L., Driffort, V., Benoist, L., Poet, M., Counillon, L., Antelmi, E., Rubino, R., Besson, P., Labbal, F., Chevalier, S., Reshkin, S.J., Gore, J. and Roger, S. (2013) NaV1.5 sodium channels allosterically regulate the NHE-1 exchanger and promote breast cancer cell invadopodial activity. J Cell Sci. Nov 1;126(Pt 21):4835-42. doi: 10.1242/jcs.123901. Epub 2013 Jul 31

Keywords: voltage-gated sodium channels, NHE-1, pH, cancer cell invasiveness, invadopodia

Conference: 4th Annual Meeting of the International Society of Proton Dynamics in Cancer, Garching, Germany, 10 Oct - 12 Oct, 2013.

Presentation Type: Abstract

Topic: 7. pH and stroma-tumor interactions, metastasis

Citation: Brisson L, Driffort V, Benoist L, Poet M, Counillon L, Antelmi E, Rubino R, Besson P, Labbal F, Chevalier S, Reshkin SJ, Goré J and Roger S (2014). NaV1.5 sodium channels increase breast cancer cell invadopodial activity by both controlling Src kinase-dependent F-actin polymerization and promoting NHE-1-dependent proton efflux and extracellular matrix digestion. Front. Pharmacol. Conference Abstract: 4th Annual Meeting of the International Society of Proton Dynamics in Cancer. doi: 10.3389/conf.fphar.2014.61.00011

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Received: 16 Dec 2013; Published Online: 07 Feb 2014.

* Correspondence: Dr. Sébastien Roger, UMR inserm 1069 Université François-Rabelais de Tours, Tours, France, sebastien.roger@univ-tours.fr