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

Abstract

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.