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Oncogene. 2019 Sep 17. doi: 10.1038/s41388-019-1004-2. [Epub ahead of print]

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

Author information

1
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, China.
2
Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, 510006, Guangdong, China.
3
Department of Medical Oncology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
4
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, Guangdong, China.
5
Department of Pathology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, China.
6
Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
7
Department of Colorectal Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, China.
8
Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA.
9
Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. skopetz@mdanderson.org.
10
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, China. xurh@sysucc.org.cn.
11
Department of Medical Oncology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China. xurh@sysucc.org.cn.
12
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, China. wangfeng@sysucc.org.cn.
13
Department of Medical Oncology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China. wangfeng@sysucc.org.cn.

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.

PMID:
31530934
DOI:
10.1038/s41388-019-1004-2

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