Role of voltage-gated sodium channel NaV1.5 and β4 auxiliary subunit in the in vitro and in vivo breast cancer cells invasiveness

L’expression anormale du canal sodique Nav1.5 dans le cancer du sein est corrélée au développement métastatique et à une mortalité augmentée. Le canal Nav1.5 est localisé dans les invadopodes des cellules cancéreuses mammaires humaines MDA-MB-231 et augmente leur activité protéolytique par une modulation allostérique de l’échangeur NHE-1 et l’activation de protéases acides. In vivo, dans un modèle de xénogreffe sur souris NMRI nude, l’expression de Nav1.5 potentialise la colonisation des poumons par les cellules cancéreuses mammaires humaines. Cette colonisation métastatique est inhibée par un traitement à la ranolazine, un inhibiteur pharmacologique des canaux Nav1.5. La sous-unité β4, auxiliaire des canaux Nav, voit son expression diminuer au cours de la progression cancéreuse, ce qui est associé in vitro à une augmentation de l’invasivité cellulaire. Cette augmentation d’invasivité semble indépendante du canal Nav1.5 et pourrait être associée à une transition des cellules vers un phénotype amiboïde. En conclusion, l’expression de Nav1.5 et la perte d’expression de β4 semblent jouer des rôles complémentaires dans l’invasivité des cellules cancéreuses.The abnormal expression of sodium channel Nav1.5 in breast cancer is correlated with metastatic development and an increased mortality. The Nav1.5 channel is located in invadopodia in human breast cancer cells MDA-MB-231, where it increases proteolytic activity by allosteric modulation of exchanger NHE-1 and activation of acidic proteases. In vivo, in a xenograft model in nude NMRI mice, the expression of Nav1.5 potentiates lung colonization by human breast cancer cells. Metastatic colonization is inhibited by treatment with ranolazine, a pharmacological inhibitor of Nav1.5. The β4 subunit, an auxiliary subunit of Nav channels, is expressed at low levels or lost when tumors are more aggressive, and its suppression in vitro increases celI invasiveness. This increase seems to be independent of Nav1.5 and could be associated with the transition of cells to an amoeboid phenotype. In conclusion, Nav1.5 expression and the loss of β4 expression seem to play complementary roles in the invasiveness of cancer cells

Ranolazine inhibits NaV1.5-mediated breast cancer cell invasiveness and lung colonization

International audienceBackground : NaV1.5 voltage-gated sodium channels are abnormally expressed in breast tumours and their expressionlevel is associated with metastatic occurrence and patients’death. In breast cancer cells, NaV1.5 activity promotes theproteolytic degradation of the extracellular matrix and enhances cell invasiveness.Findings : In this study, we showed that the extinction of NaV1.5 expression in human breast cancer cells almostcompletely abrogated lung colonisation in immunodepressed mice (NMRI nude). Furthermore, we demonstrated thatranolazine (50μM) inhibited NaV1.5 currents in breast cancer cells and reduced NaV1.5-related cancer cell invasivenessin vitro. In vivo, the injection of ranolazine (50 mg/kg/day) significantly reduced lung colonisation by NaV1.5-expressinghuman breast cancer cells.Conclusions : Taken together, our results demonstrate the importance of NaV1.5 in the metastatic colonisation oforgans by breast cancer cells and indicate that small molecules interfering with NaVactivity, such as ranolazine, mayrepresent powerful pharmacological tools to inhibit metastatic development and improve cancer treatments

SCN4B acts as a metastasis-suppressor gene preventing hyperactivation of cell migration in breast cancer

International audienceThe development of metastases largely relies on the capacity of cancer cells to invade extracellular matrices (ECM) using two invasion modes termed 'mesenchymal' and 'amoeboid', with possible transitions between these modes. Here we show that the SCN4B gene, encoding for the β4 protein, initially characterized as an auxiliary subunit of voltage-gated sodium channels (NaV) in excitable tissues, is expressed in normal epithelial cells and that reduced β4 protein levels in breast cancer biopsies correlate with high-grade primary and metastatic tumours. In cancer cells, reducing β4 expression increases RhoA activity, potentiates cell migration and invasiveness, primary tumour growth and metastatic spreading, by promoting the acquisition of an amoeboid-mesenchymal hybrid phenotype. This hyperactivated migration is independent of NaV and is prevented by overexpression of the intracellular C-terminus of β4. Conversely, SCN4B overexpression reduces cancer cell invasiveness and tumour progression, indicating that SCN4B/β4 represents a metastasis-suppressor gene