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

Brisson, Lucie;Driffort, Virginie;Benoist, Lauriane;Poet, Mallorie;Roger , Sébastien;et.al.
(2013) 4th annual meeting of the ISPDC — Location: Munich, Germany (10.October.2013)

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Authors
  • Brisson, LucieUCLouvain
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  • Driffort, VirginieUniversité de Tours
    Author
  • Benoist, LaurianeUniversité de Tours
    Author
  • Poet, MallorieUniversité de Nice-Sophia Antipolis
    Author
  • Roger , SébastienUniversité de Tours
    Author
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Abstract
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].
Affiliations
  • Université de ToursInserm U1069 Nutrition Croissance et Cancer

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Brisson, L., Driffort, V., Benoist, L., Poet, M., Counillon, L., Antelmi, E., Rubino, R., Besson, P., Labbal, F., Chevalier, S., Reshkin, S. J., Goré, J., & Roger, S. (2013). 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. Frontiers in Pharmacology. Published. 4th annual meeting of the ISPDC, Munich, Germany. https://hdl.handle.net/2078.5/52631 (Original work published 2013)