mTOR-mediated Na⁺/Ca²⁺ exchange affects cell proliferation and metastasis of melanoma cells

Melanoma is a common malignant tumor, which is associated with high mortality rate. The multiple-drug resistance of tumor cells often results in failure of chemotherapy. The aim of our study is to investigate the expression of Nav 1.6 in human melanoma cells and human epidermal melanocytes. Additionally, the effect of Na+channels on Ca+ current and mTOR activity in melanoma cells were also analyzed. The protein expression levels of Nav1.6 in human melanocyte PIG1, WM266 and WM115 cells were investigated by western blot. After treatment of Na⁺ channel inhibitor Tetroadotoxin (TTX) or mTOR inhibitor rapamycin (RAPA), the electrophysiological activity (Na+ current and Ca2+ current) in WM266 and WM115 cells was detected by patch clamp technique. The expression of mTORC1 phosphorylates S6 kinase (p-S6), cell invasion and migration, cell proliferation and cell apoptosis were also performed. Results shown that Nav 1.6 was overexpressed in WM266 and WM115 cells, and the inhibition of Na⁺ channel by TTX reduced Na⁺ current. Both TTX and RAPA suppressed Ca²⁺ current and the expression of p-S6, thus inducing Na⁺ channel which activates the mTOR-Ca2+ signaling pathway. Both TTX and RAPA suppressed cell invasion, migration and proliferation, and promoted cell apoptosis of WM266 cells. Thus, the Nav1.6 sodium channel promotes cell proliferation and invasion through mTOR-mediated Na+/Ca2+ exchange in melanoma. The observations will provide a new perspective for understanding the malignant biological behavior of melanoma cells, and potentially provide a new drug target.