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

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 survi...

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Autores principales: Li, Shuai, Zhuang, Zhuonan, Wu, Teng, Lin, Jie-Chun, Liu, Ze-Xian, Zhou, Li-Fen, Dai, Ting, Lu, Lei, Ju, Huai-Qiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079569/
https://www.ncbi.nlm.nih.gov/pubmed/30059901
http://dx.doi.org/10.1016/j.redox.2018.07.017
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author Li, Shuai
Zhuang, Zhuonan
Wu, Teng
Lin, Jie-Chun
Liu, Ze-Xian
Zhou, Li-Fen
Dai, Ting
Lu, Lei
Ju, Huai-Qiang
author_facet Li, Shuai
Zhuang, Zhuonan
Wu, Teng
Lin, Jie-Chun
Liu, Ze-Xian
Zhou, Li-Fen
Dai, Ting
Lu, Lei
Ju, Huai-Qiang
author_sort Li, Shuai
collection PubMed
description 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.
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spelling pubmed-60795692018-08-08 Nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer Li, Shuai Zhuang, Zhuonan Wu, Teng Lin, Jie-Chun Liu, Ze-Xian Zhou, Li-Fen Dai, Ting Lu, Lei Ju, Huai-Qiang Redox Biol Research Paper 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. Elsevier 2018-07-21 /pmc/articles/PMC6079569/ /pubmed/30059901 http://dx.doi.org/10.1016/j.redox.2018.07.017 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Li, Shuai
Zhuang, Zhuonan
Wu, Teng
Lin, Jie-Chun
Liu, Ze-Xian
Zhou, Li-Fen
Dai, Ting
Lu, Lei
Ju, Huai-Qiang
Nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer
title Nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer
title_full Nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer
title_fullStr Nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer
title_full_unstemmed Nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer
title_short Nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer
title_sort nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079569/
https://www.ncbi.nlm.nih.gov/pubmed/30059901
http://dx.doi.org/10.1016/j.redox.2018.07.017
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