A novel Nav1.5-dependent feedback mechanism driving glycolytic acidification in breast cancer metastasis

Abstract

AbstractSolid tumours have abnormally high intracellular [Na+]. The activity of various Na+transporting proteins including channels may underlie this Na+accumulation. Here, we show that voltage-gated Na+channels (VGSCs) are functionally active in a subset of breast cancer cell lines, cancer-associated fibroblasts, xenograft tumours and metastases. Downregulation of the Nav1.5 VGSC in xenograft breast tumours suppresses expression of invasion-regulating genes, consistent with previous studies showing that Nav1.5 promotes invasion in cancer cells. We also show that Nav1.5 activity increases glycolysis, promoting extracellular acidification that would facilitate this invasion. In a reciprocal interaction, acidic extracellular pH elevates persistent Na+influx through Nav1.5 in breast cancer cells. Using a mathematical model, we show that Nav1.5 activity can sustain production of extracellular H+. We show that likely VGSC currents are detectable in patient-derived breast tumour cells and tissues. Furthermore, protein expression of Nav1.5 strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. Together, these findings show positive feedback between extracellular acidification and movement of Na+into cancer cells which can facilitate invasion. They also highlight the clinical significance of Nav1.5 as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment.