SUCLA2-coupled regulation of GLS succinylation and activity counteracts oxidative stress in tumor cells

Yingying Tong; Dong Guo; Shu-Hai Lin; Jiazhen Liang; Dianqiang Yang; Chunmin Ma; Fei Shao; Min Li; Qiujing Yu; Yuhui Jiang; Lei Li; Jing Fang; Rilei Yu; Zhimin Lu

doi:10.1016/j.molcel.2021.04.002

SUCLA2-coupled regulation of GLS succinylation and activity counteracts oxidative stress in tumor cells

Mol Cell. 2021 Jun 3;81(11):2303-2316.e8. doi: 10.1016/j.molcel.2021.04.002. Epub 2021 May 14.

Authors

Yingying Tong¹, Dong Guo², Shu-Hai Lin³, Jiazhen Liang⁴, Dianqiang Yang³, Chunmin Ma⁵, Fei Shao⁶, Min Li², Qiujing Yu⁷, Yuhui Jiang⁵, Lei Li⁶, Jing Fang⁶, Rilei Yu⁸, Zhimin Lu⁹

Affiliations

¹ The Institute of Cell Metabolism and Diseases, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China; Cancer Center, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China.
² Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang 310029, China.
³ State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
⁴ Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China.
⁵ The Institute of Cell Metabolism and Diseases, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China.
⁶ The Affiliated Hospital of Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China.
⁷ The Institute of Cell Metabolism and Diseases, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
⁸ Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China. Electronic address: ryu@ouc.edu.cn.
⁹ Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang 310029, China. Electronic address: zhiminlu@zju.edu.cn.

PMID: 33991485
DOI: 10.1016/j.molcel.2021.04.002

Abstract

Glutaminase regulates glutaminolysis to promote cancer cell proliferation. However, the mechanism underlying glutaminase activity regulation is largely unknown. Here, we demonstrate that kidney-type glutaminase (GLS) is highly expressed in human pancreatic ductal adenocarcinoma (PDAC) specimens with correspondingly upregulated glutamine dependence for PDAC cell proliferation. Upon oxidative stress, the succinyl-coenzyme A (CoA) synthetase ADP-forming subunit β (SUCLA2) phosphorylated by p38 mitogen-activated protein kinase (MAPK) at S79 dissociates from GLS, resulting in enhanced GLS K311 succinylation, oligomerization, and activity. Activated GLS increases glutaminolysis and the production of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione, thereby counteracting oxidative stress and promoting tumor cell survival and tumor growth in mice. In addition, the levels of SUCLA2 pS79 and GLS K311 succinylation, which were mutually correlated, were positively associated with advanced stages of PDAC and poor prognosis for patients. Our findings reveal critical regulation of GLS by SUCLA2-coupled GLS succinylation regulation and underscore the regulatory role of metabolites in glutaminolysis and PDAC development.

Keywords: GLS; GSH; NADPH; SUCLA2; glutaminolysis; p38; phosphorylation; succinyl-CoA; succinylation; tumorigenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Pancreatic Ductal / diagnosis
Carcinoma, Pancreatic Ductal / enzymology
Carcinoma, Pancreatic Ductal / genetics*
Carcinoma, Pancreatic Ductal / mortality
Cell Line, Tumor
Cell Proliferation
Gene Expression Regulation, Neoplastic
Glutaminase / genetics*
Glutaminase / metabolism
Glutamine / metabolism
Glutathione / metabolism
Heterografts
Humans
Male
Mice
Mice, Nude
NADP / metabolism
Oxidative Stress
Pancreatic Neoplasms / diagnosis
Pancreatic Neoplasms / enzymology
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / mortality
Phosphorylation
Prognosis
Protein Processing, Post-Translational
Signal Transduction
Succinate-CoA Ligases / genetics*
Succinate-CoA Ligases / metabolism
Succinic Acid / metabolism
Survival Analysis
p38 Mitogen-Activated Protein Kinases / genetics
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Glutamine
NADP
Succinic Acid
p38 Mitogen-Activated Protein Kinases
GLS protein, human
GLS1 protein, mouse
Glutaminase
Succinate-CoA Ligases
SUCLA2 protein, human
Sucla2 protein, mouse
Glutathione