Endogenous and exogenous hydrogen sulfide modulates urothelial bladder carcinoma development in human cell lines

The role of H₂S in urothelial carcinoma (UC) is still unclear. Here we have evaluated the expression of H₂S producing enzymes as well as the effect of endogenous and exogenous H₂S on human bladder UC cells. In human UC cells the expression of cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST); is significantly lower as compared to healthy cells. A modulatory role for the H₂S pathway is supported by the finding that, the overexpression of CSE or CBS, but not 3-MST, inhibits cell proliferation and promotes apoptosis. A similar effect is obtained by using exogenous H₂S. Diallyl trisulfide (DATS), which is a fully characterized H₂S donor, inhibits the proliferation of UC cells in a time and concentration-dependent manner as well as promotes apoptosis. Moreover, DATS also induces autophagy, as determined by transcriptomic and western blot analysis. Finally, DATS inhibits mRNA expression levels of canonical markers of epithelial-mesenchymal transition by limiting migration and clonogenic ability of human UC cells in vitro. In conclusion, in urothelial carcinoma, there is an impairment of H₂S pathway that involves CSE and CBS- derived hydrogen sulfide. Thus, targeting H₂S signaling pathway in urothelial carcinoma could represent a novel therapeutic strategy.