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Redox Biol. 2018 Sep;18:246-255. doi: 10.1016/j.redox.2018.07.017. Epub 2018 Jul 21.

Nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer.

Author information

1
Department of Biochemistry and Molecular Biology, GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 510182, PR China.
2
Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital Medical Center, Tsinghua University, Beijing 102218, China.
3
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
4
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. Electronic address: juhq@sysucc.org.cn.

Abstract

Overcoming oxidative stress is a critical step for tumor growth and metastasis, however the underlying mechanisms in gastric cancer remain unclear. In this study, we found that overexpression of nicotinamide nucleotide transhydrogenase (NNT) was associated with shorter overall and disease free survival in gastric cancer. The NNT is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Knockdown of NNT caused significantly NADPH reduction, induced high levels of ROS and significant cell apoptosis under oxidative stress conditions such as glucose deprival and anoikis. In vivo experiments showed that NNT promoted tumor growth, lung metastasis and peritoneal dissemination of gastric cancer. Moreover, intratumoral injection of NNT siRNA significantly suppressed gastric tumor growth in patient-derived xenograft (PDX) models. Overall, our study highlights the crucial functional roles of NNT in redox regulation and tumor progression and thus raises an important therapeutic hypothesis in gastric cancer.

KEYWORDS:

Anoikis resistance; Gastric cancer; Metastasis; NADPH; NNT

PMID:
30059901
PMCID:
PMC6079569
DOI:
10.1016/j.redox.2018.07.017
[Indexed for MEDLINE]
Free PMC Article

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