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; Jun-Ping Yun; Huai Qiang Ju; Jian Xiong Feng; Dan Xie; Song Gao; Wei-Hua Jia; Scott Kopetz; Rui-Hua Xu; Feng Wang

doi:10.1038/s41388-019-1004-2

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, Jun-Ping YunHuai Qiang Ju, Jian Xiong Feng, Dan Xie, Song Gao, Wei-Hua Jia, Scott Kopetz, Rui-Hua Xu, Feng Wang

GI Medical Oncology

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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 language	English (US)
Pages (from-to)	637-650
Number of pages	14
Journal	Oncogene
Volume	39
Issue number	3
DOIs	https://doi.org/10.1038/s41388-019-1004-2
State	Published - Jan 16 2020

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

MD Anderson CCSG core facilities

Functional Proteomics Reverse Phase Protein Array Core
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10.1038/s41388-019-1004-2

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Wang, Y. N., Lu, Y. X., Liu, J., Jin, Y., Bi, H. C., Zhao, Q., Liu, Z. X., Li, Y. Q., Hu, J. J., Sheng, H., Jiang, Y. M., Zhang, C., Tian, F., Chen, Y., Pan, Z.-Z., Chen, G., Zeng, Z. L., Liu, K. Y., Ogasawara, M., ... 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, 39(3), 637-650. https://doi.org/10.1038/s41388-019-1004-2

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, Z-Z, Chen, G, Zeng, ZL, Liu, KY, Ogasawara, M, Yun, J-P, Ju, HQ, Feng, JX, Xie, D, Gao, S, Jia, W-H, Kopetz, S, Xu, R-H & 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

@article{a7bf85ac2933459bafd3989d75bdf6b7,

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

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.",

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

note = "Funding Information: Acknowledgements This study was supported, in part, by the National Key Research and Development Program of China (2017YFC1308900, 2018YFC1313300), Natural Science Foundation of Guangdong Province (2014A030312015, 2017A030313485); National Natural Science Foundation of China (81872011, 81572392); Science and Technology Program of Guangdong (2019B020227002), Science and Technology Program of Guangzhou (201904020046, 201803040019, 201704020228), Guangzhou Health and Medical Collaborative Innovation Project (201704020220), and the Sun Yat-sen University Clinical Research 5010 Program (2018014). FW is the Young Physician Scientist Program of Sun Yat-sen University Cancer Center. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2020",

month = jan,

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doi = "10.1038/s41388-019-1004-2",

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volume = "39",

pages = "637--650",

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T1 - AMPKα1 confers survival advantage of colorectal cancer cells under metabolic stress by promoting redox balance through the regulation of glutathione reductase phosphorylation

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, Jun-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

N1 - Funding Information: Acknowledgements This study was supported, in part, by the National Key Research and Development Program of China (2017YFC1308900, 2018YFC1313300), Natural Science Foundation of Guangdong Province (2014A030312015, 2017A030313485); National Natural Science Foundation of China (81872011, 81572392); Science and Technology Program of Guangdong (2019B020227002), Science and Technology Program of Guangzhou (201904020046, 201803040019, 201704020228), Guangzhou Health and Medical Collaborative Innovation Project (201704020220), and the Sun Yat-sen University Clinical Research 5010 Program (2018014). FW is the Young Physician Scientist Program of Sun Yat-sen University Cancer Center. Publisher Copyright: © 2019, The Author(s).

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.

AB - 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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JO - Oncogene

JF - Oncogene

IS - 3

ER -

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

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ASJC Scopus subject areas

MD Anderson CCSG core facilities

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