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

54 Pages Posted: 19 Dec 2018

See all articles by Rui Wang

Rui Wang

Huazhong University of Science and Technology - Tongji Hospital

Qilin Fan

Huazhong University of Science and Technology

Shengyue Wang

Huazhong University of Science and Technology - Tongji Hospital

Yinfang Hao

Huazhong University of Science and Technology - Tongji Hospital

Wei Wang

Huazhong University of Science and Technology - Tongji Hospital

Dong Shuang

Huazhong University of Science and Technology - Tongji Hospital

Zhe Wang

Huazhong University of Science and Technology - Tongji Hospital

Junjie Zhang

Huazhong University of Science and Technology - Division of Gastroenterology

Tuvshin Bao

Huazhong University of Science and Technology - Union Hospital

Xiaohui Wang

Sun Yat-sen University (SYSU) - Lingnan (University) College

Xiaoming Qiu

Gansu Provincial Hospital - Institute of Clinical Research and Translational Medicine

Kekun Wang

Wuhan University

Xinyu Mo

Tianjin University of Traditional Chinese Medicine

Yuqi Kang

Oncology Hospital of Guizhou Province

Zhirong Wang

Huazhong University of Science and Technology - Division of Gastroenterology

More...

Abstract

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.

Keywords: hydrogen sulfide, uncoupling protein 2, mitochondrial ATP, bioenergetic dysfunction, cancer spread, gastric cancer

Suggested Citation

Wang, Rui and Fan, Qilin and Wang, Shengyue and Hao, Yinfang and Wang, Wei and Shuang, Dong and Wang, Zhe and Zhang, Junjie and Bao, Tuvshin and Wang, Xiaohui and Qiu, Xiaoming and Wang, Kekun and Mo, Xinyu and Kang, Yuqi and Wang, Zhirong, Prevention of Stomach Carcinoma Spread by Induces Bioenergetic Dysfunction in UCP2-Negative Gastric Cancer Cells with Hydrogen Sulfide (October 19, 2018). Available at SSRN: https://ssrn.com/abstract=3271402 or http://dx.doi.org/10.2139/ssrn.3271402

Rui Wang

Huazhong University of Science and Technology - Tongji Hospital

1239 Siping Road
Shanghai, 200092
China

Qilin Fan

Huazhong University of Science and Technology

1037 Luoyu Rd
Wuhan, Hubei 430074
China

Shengyue Wang

Huazhong University of Science and Technology - Tongji Hospital

1239 Siping Road
Shanghai, 200092
China

Yinfang Hao

Huazhong University of Science and Technology - Tongji Hospital

1239 Siping Road
Shanghai, 200092
China

Wei Wang

Huazhong University of Science and Technology - Tongji Hospital

1239 Siping Road
Shanghai, 200092
China

Dong Shuang

Huazhong University of Science and Technology - Tongji Hospital

1239 Siping Road
Shanghai, 200092
China

Zhe Wang

Huazhong University of Science and Technology - Tongji Hospital

1239 Siping Road
Shanghai, 200092
China

Junjie Zhang

Huazhong University of Science and Technology - Division of Gastroenterology

Wuhan
China

Tuvshin Bao

Huazhong University of Science and Technology - Union Hospital ( email )

Wuhan
China

Xiaohui Wang

Sun Yat-sen University (SYSU) - Lingnan (University) College ( email )

135, Xingang Xi Road
Guangzhou, Guangdong 510275
China

Xiaoming Qiu

Gansu Provincial Hospital - Institute of Clinical Research and Translational Medicine

China

Kekun Wang

Wuhan University

Wuhan
China

Xinyu Mo

Tianjin University of Traditional Chinese Medicine

Tianjin
China

Yuqi Kang

Oncology Hospital of Guizhou Province

Guiyang
China

Zhirong Wang (Contact Author)

Huazhong University of Science and Technology - Division of Gastroenterology ( email )

Wuhan
China