Prevention of Stomach Carcinoma Spread by Induces Bioenergetic Dysfunction in UCP2-Negative Gastric Cancer Cells with Hydrogen Sulfide

Background: Metabolite profiling stratifies gastric cancer (GC) cells into subtypes with distinct sensitivities to metabolic inhibitors. Hydrogen sulfide (H2S), an obvious characteristic is selectively suppressing cancer spread. However, it intrigues broad interest to explore the clinical benefits of cancer therapy, with the current understanding of molecular mechanisms of H2S which remains unknown. Methods: Transcriptome analysis identified that H2S inhibited uncoupling protein 2 (UCP2)-negative GC cells spread in cells cultures and animal models. The levels of bioenergetic function and proton leak was assayed by real-time bioenergetic analyzer. Metabolomics profiling revealed that H2S disturbed palmitic acid beta-oxidation to inhibitory of mitochondrial ATP (mitoATP) synthesis. Liquid chromatograph-mass spectrometer (LC-MS) and Chromatin Immunoprecipitation (ChIP) evaluated H2S promoted POZ/BTB family protein-33 (ZBTB33) nuclear translocation. Results: H2S promotes ZBTB33 nuclear translocation, and up-regulates UCP2 expression at the level of gene and protein in UCP2-negative GC cells. H2S triggers proton leak and turn off the metabolic switch that is essential for GC spread. Functional analysis showed repressed mitoATP synthesis, correlated negatively with ROS-mTOR signaling pathway, activated Casp8, and induced cell death in UCP2-negative GC cells following overexpression of UCP2. H2S reinforces that UCP2 catalyzes respiratory chain uncoupling by an H -assisted mechanism. Interpretation: Our preclinical work showed UCP2-negative GC cells into subtypes with distinct sensitivities to lipid inhibitor in drug discovery for screening chemopreventive agents against GC. We additionally demonstrate that the expression of UCP2 in GC served as a prognostic biomarker and negatively correlated with recurrence of de novo GC after curative treatment. Funding Statement: This work was supported by the Strategic Priority Research Program of the Science and Technology Commission of Shanghai (1312JC1408402 for Zhirong Wang). Declaration of Interests: No potential conflicts of interest were disclosed. Ethics Approval Statement: This animal study was conducted in accordance with the rules and regulations of the Institutional Animal Care and Use Committee (IACUC) at the Department of Laboratory Animal Science, Fudan University (Shanghai, P.R. China). Informed consent was approved by the Ethics Committees of Tongji Hospital and all subjects gave written informed consent.