title: NaV1.5 Na⁺ channels allosterically regulate the NHE-1 exchanger and promote the activity of breast cancer cell invadopodia.
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 MDA-MB-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.
authors.affiliation: Inserm U1069, Nutrition, Croissance et Cancer, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Brisson
authors.forename: Virginie
authors.initials: V
authors.lastname: Driffort
authors.forename: Lauriane
authors.initials: L
authors.lastname: Benoist
authors.forename: Mallorie
authors.initials: M
authors.lastname: Poet
authors.forename: Laurent
authors.initials: L
authors.lastname: Counillon
authors.forename: Ester
authors.initials: E
authors.lastname: Antelmi
authors.forename: Rosa
authors.initials: R
authors.lastname: Rubino
authors.forename: Pierre
authors.initials: P
authors.lastname: Besson
authors.forename: Fabien
authors.initials: F
authors.lastname: Labbal
authors.forename: Stéphan
authors.initials: S
authors.lastname: Chevalier
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Reshkin
authors.forename: Jacques
authors.initials: J
authors.lastname: Gore
authors.forename: Sébastien
authors.initials: S
authors.lastname: Roger
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D022081:Cell Surface Extensions / Q000235:genetics / Q000378:metabolism*; D051356:Cortactin / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; D051356:Cortactin; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1
keywords: Cancer cell invasiveness; Caveolae; Invadopodia; Na+/H+ exchanger type 1; SCN5A; Voltage-gated Na+ channels