H2S induces apoptosis of tumors with high IDO1 expression via NR4A1-BCL-2 and SOCS3 pathways.

Hydrogen sulfide (H2S) has been reported to exert both protumor and antitumor functions. It is worthy to clarify the condition under which H2S exerts antitumor effects and its underlying mechanism. Our previous study connected the immune checkpoint indoleamine 2,3-dioxygenase 1 (IDO1) and H2S by revealing that H2S downregulates IDO1 expression, leading to our hypothesis that antitumor effect of H2S is associated with IDO1 expression in tumor cells. Apoptosis, cellular distribution of NR4A1, phosphorylation of IDO1, and the binding of phosphorylated IDO1 and SOCS3 are examined both in vitro and in vivo. In this study, we confirm our hypothesis by showing that H2S significantly reduces proliferation and induces apoptosis of tumor cells with high IDO1 expression. In tumor cells with high IDO1 expression, H2S promotes the translocation of NR4A1 out of nucleus and its binding with BCL-2, as well as the phosphorylation of IDO1 and the codegradation of phosphorylated IDO1 and SOCS3. Such mechanism by which H2S induces apoptosis of tumors with high IDO1 expression is also elucidated in tumor-bearing mice, where H2S shows great therapeutic effect against tumors with high IDO1 expression. H2S induces apoptosis of tumor cells with high expression of IDO1 by promoting NR4A1-BCL-2 apoptotic pathway and the codegradation of phosphorylated IDO1 and SOCS3. Our study provides new theoretical and experimental evidence for a strategy for tumor therapy with H2S.