ArticleThe Journal of clinical investigation2022
Glutamine synthetase limits β-catenin-mutated liver cancer growth by maintaining nitrogen homeostasis and suppressing mTORC1.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
55 citing papers in PubMed, 61 citations in OpenAlex.
- Diammonium phosphate supplementation in low-protein diets improves nitrogen utilization and feed efficiency without impairing carcass traits or meat quality in finishing pigs.Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2026Article
- Glutamine metabolism in health and disease.Signal transduction and targeted therapy · 2026Review
- A novel glutamine metabolism-based classification system for characterizing the heterogeneity of hepatocellular carcinoma.Journal of gastrointestinal oncology · 2026Article
- Alcohol reshapes liver zonal plasticity and immune-metabolic reprogramming in metabolic-syndrome associated hepatocellular carcinoma.Nature communications · 2026Article
- Localized Intratumoral Ammonium Hydroxide Administration Demonstrates Changes in Tumor Architecture and Renal Response in a Murine Breast Cancer Xenograft Model.Current issues in molecular biology · 2026Article
- Mesenchymal stromal cells ameliorate hyperammonemia in acute hepatic failure via inhibiting glutaminolysis.Chinese medical journal · 2026Article
- ABCC2 as a novel therapeutic target in lung adenocarcinoma: a machine learning-driven discovery linking ammonia metabolism to prognosis and drug resistance.Journal of translational medicine · 2026Article
- The evolving role of OMICS in gastrointestinal tumor biology and clinical practice.Molecular cancer · 2026Review
- Dietary polyphenols and hepatocellular carcinoma: protective mechanisms, challenges, and future directions.Discover oncology · 2026Review
- WNT-β-catenin signalling in hepatocellular carcinoma: from bench to clinical trials.Nature reviews. Gastroenterology & hepatology · 2026Review
- The origin of hepatocellular carcinoma depends on metabolic zonation.Science (New York, N.Y.) · 2026Article
- RHOJ derived peptide promotes chemosensitivity by inhibiting glutamine metabolism in gastric cancer.Journal of translational medicine · 2026Article
- Impaired nitrogenous waste clearance promotes hepatocellular carcinoma.Science advances · 2026Article
- The Role of Mitochondrial Dysfunction in Hepatocellular Carcinoma: From Pathogenesis and Drug Resistance to Targeted Therapeutic Strategies.Journal of hepatocellular carcinoma · 2026Review
- Immunometabolic Reprogramming in Hepatocellular Carcinoma Mechanisms, Biomarkers, and Therapeutic Implications.Oncology research · 2026Review
- Amino Acid Metabolism in Chronic Liver Disease: from Pathogenic Driver to Therapeutic Target.International journal of biological sciences · 2026Review
- Letter to the editor on "GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma".Clinical and molecular hepatology · 2026Article
- Ammonia signaling network: the intersection of tumor metabolism, epigenetics, and metastasis.Frontiers in endocrinology · 2026Review
- Correspondence to letter to the editor on "GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma".Clinical and molecular hepatology · 2026Article
- Ammonium Hydroxide Enhancement of Dietary Protein in High-Fat Diets Modulates Liver Metabolism Signaling in a Sex- and Age-Dependent Manner in C3H/HeJ Mice.International journal of molecular sciences · 2025Article
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 2 countries.
Funding
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.
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