Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Glutamine synthetase limits β-catenin–mutated liver cancer growth by maintaining nitrogen homeostasis and suppressing mTORC1
Weiwei Dai, … , Shenglan Gao, Wei-Xing Zong
Weiwei Dai, … , Shenglan Gao, Wei-Xing Zong
Published October 18, 2022
Citation Information: J Clin Invest. 2022;132(24):e161408. https://doi.org/10.1172/JCI161408.
View: Text | PDF
Research Article Hepatology Metabolism Article has an altmetric score of 5

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

  • Text
  • PDF
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.

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

×

Figure 1

Hepatic ablation of GS exacerbates HCC development driven by c-Met/ΔN90-β-catenin.

Options: View larger image (or click on image) Download as PowerPoint
Hepatic ablation of GS exacerbates HCC development driven by c-Met/ΔN90-...
Seven-week-old Glulfl/fl Alb-Cre– (WT) and Glulfl/fl Alb-Cre+ (KO) male mice were injected with either vehicle or c-Met/ΔN90-β-catenin/SB10 plasmids via SB-HTVI. Livers were collected and analyzed at the indicated time intervals. (A) Immunoblotting of liver tissue samples collected at 6 weeks (endpoint of the KO mice) after HTVI. Representative blots are shown (n = 3–5). The protein molecular weight in kDa is indicated on the left. (B) Relative mRNA levels in livers 2 weeks after HTVI were determined by qPCR (n = 3–4). (C) IHC of GS was performed at 0, 2, or 6 weeks after HTVI (n = 3). Representative images are shown. (D) Liver/body weight ratios were compared (n = 3–6). (E) Kaplan-Meier curves are shown. (F) Representative gross, H&E, and IHC images of liver tissues harvested 6 weeks after oncogene injection (n = 3). (G and H) Seven-week-old Glulfl/fl male mice were first coinjected with pCMV-c-Met/ΔN90-β-catenin plasmids. One week later, half of the mice were randomly selected and injected with adenoviral CMV-Cre (Ad-Cre), while the other half were injected with adenoviral CMV-GFP (Ad-GFP) as controls via the tail vein. Livers were harvested another 7 days later, and immunoblotting showed successful GS knockout by Ad-Cre (G). Mice were harvested at the endpoint (6 weeks after HTVI injection) (n = 6). Liver weight/body weight ratios were compared. The results are expressed as mean ± SEM (H). (I) Liver sections from WT and KO mice were obtained at the indicated time points and processed for H&E and PCNA IHC staining (n = 3 mice for each group). Representative images are shown. The number of PCNA-positive cells was quantified by ImageJ from 6 randomly selected fields. Shown on the right is the mean percentage ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 2-tailed t test (B, D, and I). NS, not significant. Scale bars: 100 μm (C and F [right]), 1 cm (F, left), and 50 μm (I).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 9 X users
22 readers on Mendeley
See more details