AMPKα1 confers survival advantage of colorectal cancer cells under metabolic stress by promoting redox balance through the regulation of glutathione reductase phosphorylation

Ying Nan Wang, Yun Xin Lu, Jie Liu, Ying Jin, Hui Chang Bi, Qi Zhao, Ze Xian Liu, Ying Qin Li, Jia Jia Hu, Hui Sheng, Yi Ming Jiang, Chao Zhang, Feng Tian, Yang Chen, Zhi Zhong Pan, Gong Chen, Zhao Lei Zeng, Kai Yan Liu, Marcia Ogasawara, Jin Ping YunHuai Qiang Ju, Jian Xiong Feng, Dan Xie, Song Gao, Wei Hua Jia, Scott Kopetz, Rui Hua Xu, Feng Wang

Research output: Contribution to journalArticle

Abstract

Patients with stage II or III colorectal cancer (CRC) exhibit various clinical outcomes after radical treatments. The 5-year survival rate was between 50 and 87%. However, the underlying mechanisms of the variation remain unclear. Here we show that AMPKα1 is overexpressed in CRC patient specimens and the high expression is correlated with poor patient survival. We further reveal a previously unrecognized function of AMPKα1, which maintains high level of reduced glutathione to keep reduction–oxidation reaction (redox) homeostasis under stress conditions, thus promoting CRC cell survival under metabolic stress in vitro and enhancing tumorigenesis in vivo. Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity. Suppression of AMPKα1 by using nano-sized polymeric vector induces a favorable therapeutic effect, especially when in combination with oxaliplatin. Our study uncovers a novel function of AMPKα1 in redox regulation and identifies a promising therapeutic strategy for treatment of CRC.

Original languageEnglish (US)
Pages (from-to)637-650
Number of pages14
JournalOncogene
Volume39
Issue number3
DOIs
StatePublished - Jan 16 2020

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Physiological Stress
Glutathione Reductase
Colorectal Neoplasms
Phosphorylation
oxaliplatin
Survival
Therapeutic Uses
Glutathione
Cell Survival
Carcinogenesis
Homeostasis
Therapeutics
Survival Rate

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

AMPKα1 confers survival advantage of colorectal cancer cells under metabolic stress by promoting redox balance through the regulation of glutathione reductase phosphorylation. / Wang, Ying Nan; Lu, Yun Xin; Liu, Jie; Jin, Ying; Bi, Hui Chang; Zhao, Qi; Liu, Ze Xian; Li, Ying Qin; Hu, Jia Jia; Sheng, Hui; Jiang, Yi Ming; Zhang, Chao; Tian, Feng; Chen, Yang; Pan, Zhi Zhong; Chen, Gong; Zeng, Zhao Lei; Liu, Kai Yan; Ogasawara, Marcia; Yun, Jin Ping; Ju, Huai Qiang; Feng, Jian Xiong; Xie, Dan; Gao, Song; Jia, Wei Hua; Kopetz, Scott; Xu, Rui Hua; Wang, Feng.

In: Oncogene, Vol. 39, No. 3, 16.01.2020, p. 637-650.

Research output: Contribution to journalArticle

Wang, YN, Lu, YX, Liu, J, Jin, Y, Bi, HC, Zhao, Q, Liu, ZX, Li, YQ, Hu, JJ, Sheng, H, Jiang, YM, Zhang, C, Tian, F, Chen, Y, Pan, ZZ, Chen, G, Zeng, ZL, Liu, KY, Ogasawara, M, Yun, JP, Ju, HQ, Feng, JX, Xie, D, Gao, S, Jia, WH, Kopetz, S, Xu, RH & Wang, F 2020, 'AMPKα1 confers survival advantage of colorectal cancer cells under metabolic stress by promoting redox balance through the regulation of glutathione reductase phosphorylation', Oncogene, vol. 39, no. 3, pp. 637-650. https://doi.org/10.1038/s41388-019-1004-2
Wang, Ying Nan ; Lu, Yun Xin ; Liu, Jie ; Jin, Ying ; Bi, Hui Chang ; Zhao, Qi ; Liu, Ze Xian ; Li, Ying Qin ; Hu, Jia Jia ; Sheng, Hui ; Jiang, Yi Ming ; Zhang, Chao ; Tian, Feng ; Chen, Yang ; Pan, Zhi Zhong ; Chen, Gong ; Zeng, Zhao Lei ; Liu, Kai Yan ; Ogasawara, Marcia ; Yun, Jin Ping ; Ju, Huai Qiang ; Feng, Jian Xiong ; Xie, Dan ; Gao, Song ; Jia, Wei Hua ; Kopetz, Scott ; Xu, Rui Hua ; Wang, Feng. / AMPKα1 confers survival advantage of colorectal cancer cells under metabolic stress by promoting redox balance through the regulation of glutathione reductase phosphorylation. In: Oncogene. 2020 ; Vol. 39, No. 3. pp. 637-650.
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abstract = "Patients with stage II or III colorectal cancer (CRC) exhibit various clinical outcomes after radical treatments. The 5-year survival rate was between 50 and 87{\%}. However, the underlying mechanisms of the variation remain unclear. Here we show that AMPKα1 is overexpressed in CRC patient specimens and the high expression is correlated with poor patient survival. We further reveal a previously unrecognized function of AMPKα1, which maintains high level of reduced glutathione to keep reduction–oxidation reaction (redox) homeostasis under stress conditions, thus promoting CRC cell survival under metabolic stress in vitro and enhancing tumorigenesis in vivo. Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity. Suppression of AMPKα1 by using nano-sized polymeric vector induces a favorable therapeutic effect, especially when in combination with oxaliplatin. Our study uncovers a novel function of AMPKα1 in redox regulation and identifies a promising therapeutic strategy for treatment of CRC.",
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AU - Wang, Ying Nan

AU - Lu, Yun Xin

AU - Liu, Jie

AU - Jin, Ying

AU - Bi, Hui Chang

AU - Zhao, Qi

AU - Liu, Ze Xian

AU - Li, Ying Qin

AU - Hu, Jia Jia

AU - Sheng, Hui

AU - Jiang, Yi Ming

AU - Zhang, Chao

AU - Tian, Feng

AU - Chen, Yang

AU - Pan, Zhi Zhong

AU - Chen, Gong

AU - Zeng, Zhao Lei

AU - Liu, Kai Yan

AU - Ogasawara, Marcia

AU - Yun, Jin Ping

AU - Ju, Huai Qiang

AU - Feng, Jian Xiong

AU - Xie, Dan

AU - Gao, Song

AU - Jia, Wei Hua

AU - Kopetz, Scott

AU - Xu, Rui Hua

AU - Wang, Feng

PY - 2020/1/16

Y1 - 2020/1/16

N2 - Patients with stage II or III colorectal cancer (CRC) exhibit various clinical outcomes after radical treatments. The 5-year survival rate was between 50 and 87%. However, the underlying mechanisms of the variation remain unclear. Here we show that AMPKα1 is overexpressed in CRC patient specimens and the high expression is correlated with poor patient survival. We further reveal a previously unrecognized function of AMPKα1, which maintains high level of reduced glutathione to keep reduction–oxidation reaction (redox) homeostasis under stress conditions, thus promoting CRC cell survival under metabolic stress in vitro and enhancing tumorigenesis in vivo. Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity. Suppression of AMPKα1 by using nano-sized polymeric vector induces a favorable therapeutic effect, especially when in combination with oxaliplatin. Our study uncovers a novel function of AMPKα1 in redox regulation and identifies a promising therapeutic strategy for treatment of CRC.

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