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Glutamine synthetase limits β-catenin–mutated liver cancer growth by maintaining nitrogen homeostasis and suppressing mTORC1

Authors :
Weiwei Dai
Jianliang Shen
Junrong Yan
Alex J. Bott
Sara Maimouni
Heineken Q. Daguplo
Yujue Wang
Khoosheh Khayati
Jessie Yanxiang Guo
Lanjing Zhang
Yongbo Wang
Alexander Valvezan
Wen-Xing Ding
Xin Chen
Xiaoyang Su
Shenglan Gao
Wei-Xing Zong
Source :
The Journal of Clinical Investigation, Vol 132, Iss 24 (2022)
Publication Year :
2022
Publisher :
American Society for Clinical Investigation, 2022.

Abstract

Glutamine synthetase (GS) catalyzes de novo synthesis of glutamine that facilitates cancer cell growth. In the liver, GS functions next to the urea cycle to remove ammonia waste. As a dysregulated urea cycle is implicated in cancer development, the impact of GS’s ammonia clearance function has not been explored in cancer. Here, we show that oncogenic activation of β-catenin (encoded by CTNNB1) led to a decreased urea cycle and elevated ammonia waste burden. While β-catenin induced the expression of GS, which is thought to be cancer promoting, surprisingly, genetic ablation of hepatic GS accelerated the onset of liver tumors in several mouse models that involved β-catenin activation. Mechanistically, GS ablation exacerbated hyperammonemia and facilitated the production of glutamate-derived nonessential amino acids, which subsequently stimulated mechanistic target of rapamycin complex 1 (mTORC1). Pharmacological and genetic inhibition of mTORC1 and glutamic transaminases suppressed tumorigenesis facilitated by GS ablation. While patients with hepatocellular carcinoma, especially those with CTNNB1 mutations, have an overall defective urea cycle and increased expression of GS, there exists a subset of patients with low GS expression that is associated with mTORC1 hyperactivation. Therefore, GS-mediated ammonia clearance serves as a tumor-suppressing mechanism in livers that harbor β-catenin activation mutations and a compromised urea cycle.

Subjects

Subjects :
Hepatology
Metabolism
Medicine

Details

Language :
English
ISSN :
15588238
Volume :
132
Issue :
24
Database :
Directory of Open Access Journals
Journal :
The Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
edsdoj.6e32c682ad14bdb96a55a2eddeab428
Document Type :
article
Full Text :
https://doi.org/10.1172/JCI161408