NaV1.5 Na+ channels allosterically regulate the NHE-1 exchanger and promote the activity of breast cancer cell invadopodia

Lucie Brisson, Virginie Driffort, Lauriane Benoist, Mallorie Poet, Laurent Counillon, Ester Antelmi, Rosa Rubino, Pierre Besson, Fabien Labbal, Stéphan Chevalier, Stephan J. Reshkin, Jacques Gore, Sébastien Roger

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Abstract

The degradation of the extracellular matrix by cancer cells represents an essential step in metastatic progression and this is performed by cancer cell structures called invadopodia. NaV1.5 (also known as SCN5A) Na+ channels are overexpressed in breast cancer tumours and are associated with metastatic occurrence. It has been previously shown that NaV1.5 activity enhances breast cancer cell invasiveness through perimembrane acidification and subsequent degradation of the extracellular matrix by cysteine cathepsins. Here, we show that NaV1.5 colocalises with Na+/H+ exchanger type 1 (NHE-1) and caveolin-1 at the sites of matrix remodelling in invadopodia of MDAMB-231 breast cancer cells. NHE-1, NaV1.5 and caveolin-1 co-immunoprecipitated, which indicates a close association between these proteins. We found that the expression of NaV1.5 was responsible for the allosteric modulation of NHE-1, rendering it more active at the intracellular pH range of 6.4-7; thus, it potentially extrudes more protons into the extracellular space. Furthermore, NaV1.5 expression increased Src kinase activity and the phosphorylation (Y421) of the actin-nucleation-promoting factor cortactin, modified F-actin polymerisation and promoted the acquisition of an invasive morphology in these cells. Taken together, our study suggests that NaV1.5 is a central regulator of invadopodia formation and activity in breast cancer cells.

Original languageEnglish
Pages (from-to)4835-4842
Number of pages8
JournalJournal of Cell Science
Volume126
Issue number21
DOIs
Publication statusPublished - Nov 1 2013

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Sodium-Hydrogen Antiporter
Breast Neoplasms
Caveolin 1
Extracellular Matrix
Actins
Cortactin
Cathepsins
src-Family Kinases
Extracellular Space
Polymerization
Cysteine
Podosomes
Protons
Neoplasms
Phosphorylation
Proteins

Keywords

  • Cancer cell invasiveness
  • Caveolae
  • Invadopodia
  • Na/H exchanger type 1
  • SCN5A
  • Voltage-gated Na channels

ASJC Scopus subject areas

  • Cell Biology

Cite this

Brisson, L., Driffort, V., Benoist, L., Poet, M., Counillon, L., Antelmi, E., ... Roger, S. (2013). NaV1.5 Na+ channels allosterically regulate the NHE-1 exchanger and promote the activity of breast cancer cell invadopodia. Journal of Cell Science, 126(21), 4835-4842. https://doi.org/10.1242/jcs.123901

NaV1.5 Na+ channels allosterically regulate the NHE-1 exchanger and promote the activity of breast cancer cell invadopodia. / Brisson, Lucie; Driffort, Virginie; Benoist, Lauriane; Poet, Mallorie; Counillon, Laurent; Antelmi, Ester; Rubino, Rosa; Besson, Pierre; Labbal, Fabien; Chevalier, Stéphan; Reshkin, Stephan J.; Gore, Jacques; Roger, Sébastien.

In: Journal of Cell Science, Vol. 126, No. 21, 01.11.2013, p. 4835-4842.

Research output: Contribution to journalArticle

Brisson, L, Driffort, V, Benoist, L, Poet, M, Counillon, L, Antelmi, E, Rubino, R, Besson, P, Labbal, F, Chevalier, S, Reshkin, SJ, Gore, J & Roger, S 2013, 'NaV1.5 Na+ channels allosterically regulate the NHE-1 exchanger and promote the activity of breast cancer cell invadopodia', Journal of Cell Science, vol. 126, no. 21, pp. 4835-4842. https://doi.org/10.1242/jcs.123901
Brisson, Lucie ; Driffort, Virginie ; Benoist, Lauriane ; Poet, Mallorie ; Counillon, Laurent ; Antelmi, Ester ; Rubino, Rosa ; Besson, Pierre ; Labbal, Fabien ; Chevalier, Stéphan ; Reshkin, Stephan J. ; Gore, Jacques ; Roger, Sébastien. / NaV1.5 Na+ channels allosterically regulate the NHE-1 exchanger and promote the activity of breast cancer cell invadopodia. In: Journal of Cell Science. 2013 ; Vol. 126, No. 21. pp. 4835-4842.
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