H2S suppresses indoleamine 2, 3-dioxygenase 1 and exhibits immunotherapeutic efficacy in murine hepatocellular carcinoma

作者：Dan Yang, Tianqi Li, Yinlong Li, Shengnan Zhang, Weirui Li, Heng Liang, Zikang Xing, Lisha Du, Jinchao He, Chunxiang Kuang, Qing Yang · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2019 · DOI：10.1186/s13046-019-1083-5 · 被引用次数：37 · 研究领域：Sulfur Compounds in Biology、Tryptophan and brain disorders、Circadian rhythm and melatonin

Over-expression and over-activation of immunosuppressive enzyme indoleamine 2, 3 -dioxygenase 1 (IDO1) is a key mechanism of cancer immune escape. However, the regulation of IDO1 has not been fully studied. The relation between hydrogen sulfide (H 2 S) and IDO1 is unclear. The influences of endogenous and exogenous H 2 S on the expression of IDO1, iNOS and NF-κB and STAT3 signaling proteins were investigated using qPCR or western blot, and the production of nitric oxide (NO) was analyzed by nitrate/nitrite assay in Cse −/− mice and MCF-7 and SGC-7901 cells. The effect of H 2 S on IDO1 activity was investigated by HPLC and in-vitro enzymatic assay. The effect of H 2 S on tryptophan metabolism was tested by luciferase reporter assay in MCF-7 and SGC-7901 cells. The correlation between H 2 S-generating enzyme CSE and IDO1 was investigated by immunostaining and heatmaps analysis in clinical specimens and tissue arrays of hepatocellular carcinoma (HCC) patients. The immunotherapeutic effects of H 2 S on H22 HCC-bearing mice were investigated. Using Cse −/− mice, we found that H 2 S deficiency increased IDO1 expression and activity, stimulated NF-κB and STAT3 pathways and decreased the expression of NO-generating enzyme Inos . Using IDO1-expressing MCF-7 and SGC-7901 cells, we found that exogenous H 2 S inhibited IDO1 expression by blocking STAT3 and NF-κB pathways, and decreased IDO1 activity via H 2 S/NO crosstalk, and combinedly decreased the tryptophan metabolism. The negative ...