NaV1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H+ efflux in caveolae

NaV1.5 sodium channels enhance the invasiveness of breast cancer cells through the acidic-dependent activation of cysteine cathepsins. Here, we showed that the Na+/H+ exchanger type 1 (NHE1) was an important regulator of H+ efflux in breast cancer cells MDA-MB-231 and that its activity was increased by NaV1.5. NaV1.5 and NHE1 were colocalized in membrane rafts containing caveolin-1. The inhibition of NaV1.5 or NHE1 induced a similar reduction in cell invasiveness and extracellular matrix degradation; no additive effect was observed when they were simultaneously inhibited. Our study suggests that NaV1.5 and NHE1 are functionally coupled and enhance the invasiveness of cancer cells by increasing H+ efflux.