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

Background: 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.

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

Methods: 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).

Results: 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.

Conclusion: 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.

Apoptosis; Calcium overload; Melanoma; Oxidative stress; Thiotaurine.