Liver-Type Glutaminase GLS2 Is a Druggable Metabolic Node in Luminal-Subtype Breast Cancer
Open accessAbstract
Efforts to target glutamine metabolism for cancer therapy have focused on the glutaminase isozyme GLS. The importance of the other isozyme, GLS2, in cancer has remained unclear, and it has been described as a tumor suppressor in some contexts. Here, we report that GLS2 is upregulated and essential in luminal-subtype breast tumors, which account for >70% of breast cancer incidence. We show that GLS2 expression is elevated by GATA3 in luminal-subtype cells but suppressed by promoter methylation in basal-subtype cells. Although luminal breast cancers resist GLS-selective inhibitors, we find that they can be targeted with a dual-GLS/GLS2 inhibitor. These results establish a critical role for GLS2 in mammary tumorigenesis and advance our understanding of how to target glutamine metabolism in cancer.
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GLSs have at least three isoforms, GLS1, GLS2, and GAC, all localized in mitochondria.
“GLSs have at least three isoforms, GLS1, GLS2, and GAC (a splicing isoform of GLS1), all of which were recently reported to be localized in mitochondria18–20.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [20]
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Glutaminase - A potential target for cancer treatment
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Self-citationThe role of glutamine metabolism in castration-resistant prostate cancer
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Mitochondrial inhibitors: a new horizon in breast cancer therapy
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Progress in Metabolic Studies of Gastric Cancer and Therapeutic Implications
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Nuclear Receptor-Mediated Metabolic Reprogramming and the Impact on HR+ Breast Cancer
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The Metabolic Landscape of Breast Cancer and Its Therapeutic Implications
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Protein-Metabolite Interactomics Reveals Novel Regulation of Carbohydrate MetabolismPreprint
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Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns
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Glutaminolysis is a Potential Therapeutic Target for Kidney Diseases
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Deciphering the landscape of allosteric glutaminase 1 inhibitors as anticancer agents
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Glutaminase 2 as a therapeutic target in glioblastoma
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Metabolic Stress Adaptations Underlie Mammary Gland Morphogenesis and Breast Cancer Progression
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A whole food, plant-based diet reduces amino acid levels in patients with metastatic breast cancer
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Metabolic targeting of malignant tumors: a need for systemic approach
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Glutamine metabolism is essential for coronavirus replication in host cells and in mice
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Metabolic reprogramming enhances oxidative stress resistance in differentiating cardiomyocytes
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Inhibiting Glutamine Metabolism Blocks Coronavirus Replication in Mammalian CellsPreprint
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Self-citationReprogramming of amino acid metabolism in breast cancer
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Metabolic Vulnerabilities as a Therapeutic Target in Breast Cancer
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Amino acids and their roles in tumor immunotherapy of breast cancer
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Catabolism of extracellular glutathione supplies amino acids to support tumor growthPreprint
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Targeting the Glutaminolysis Pathway in Glaucoma-Associated Fibrosis
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Structural reassignment of compound 968, an allosteric glutaminase inhibitor
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Targeting Glutaminase Isoforms GLS and GLS2 in Luminal Breast Cancer
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Role of L-glutamine in the regulation of rat Sertoli cell proliferation by FSH
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Erastin-like anti-Warburg compounds X1 and X4 are GLS2-selective covalent glutaminase inhibitorsPreprint
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Decoding Metabolic Changes in Cancer Cells Resistant to Therapy
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EVT-701 : targeting electron transport chain complex I as therapeutic approach in cancer
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- Authors
- Lukey, M. J., Cluntun, A. A., Katt, W. P., Lin, M.-C. J., Druso, J. E., Ramachandran, S., Erickson, J. W., Le, H. H., Wang, Z.-E., Blank, B., Greene, K. S., & Cerione, R. A.
- Affiliations
- Cornell University (US)
- Corresponding author
- Cerione, Richard A.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 29
- Issue
- 1
- Pages
- 76-88.e7
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6939472
- OpenAlex
- W2978965391
- Cited by
- 103
- References
- 41
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 21 · 2023: 17 · 2022: 13 · 2021: 17 · 2020: 13 · 2019: 2
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- King Abdullah International Medical Research Center
- Ministry of National Guard Health Affairs
- National Institutes of Health (GM122575, CA201402)
- Breast Cancer Coalition of Rochester
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- GLS2, glutaminase, luminal breast cancer, glutamine metabolism, GATA3, promoter methylation, mammary carcinogenesis, cancer metabolism, therapeutic target
- MeSH terms
- Animals, Breast Neoplasms, Cell Line, Female, Glutaminase, Glutamine, Humans, Liver, Promoter Regions, Genetic, Genes, Tumor Suppressor, DNA Methylation, Cell Line, Tumor, GATA3 Transcription Factor, Mice, HEK293 Cells, MCF-7 Cells, Carcinogenesis
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