Thiotaurine inhibits melanoma progression by enhancing Ca²⁺ overload-induced cellular apoptosis

Melanoma is the most dangerous type of skin cancer with poor therapy outcomes. Since malignant cells are more susceptible to Ca²⁺ overload than normal cells, activating Ca²⁺ overload-mediated apoptosis may be a promising strategy to inhibit melanoma progression. Hydrogen sulfide (H₂S) donors can regulate Ca²⁺ channels, but their effects on melanoma cells remain unclear.

To explore the effects of Thiotaurine (TTAU), an H₂S donor, on melanoma cells and its underlying mechanisms.

We tested the effect of TTAU by culturing melanoma cells in vitro and establishing the xenograft model of mice in vivo. Cell proliferation and apoptosis were assessed using the CCK-8 test and flow cytometry. Molecules involved in apoptosis or Ca²⁺-related signal transduction were analyzed by western blotting. Immunofluorescence was used to measure Ca²⁺ levels, mitochondrial damage, and reactive oxygen species (ROS).

TTAU significantly reduced melanoma cell viability and induced apoptosis both in vitro and in vivo. Mechanistically, TTAU increased intracellular Ca²⁺, upregulated transient receptor potential vanilloid 1(TRPV1), and decreased activating transcription factor 3(ATF3) by nuclear factor of activated T cell cytoplasmic 1(NFATc1). TTAU also caused mitochondrial damage and ROS overproduction, which also promoted apoptosis.

We first elucidate that TTAU inhibits melanoma progression by activating Ca²⁺ influx-NFATc1-ATF3 signaling and aggravating mitochondrial oxidative stress, in which TRPV1 may act as an amplifier for Ca²⁺ influx. Our research is expected to provide new ideas for the treatment of tumors such as melanoma, as well as the clinical application of reactive sulfur species-based drugs.