Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass
Open accessAbstract
Ammonia is a ubiquitous by-product of cellular metabolism; however, the biological consequences of ammonia production are not fully understood, especially in cancer. We found that ammonia is not merely a toxic waste product but is recycled into central amino acid metabolism to maximize nitrogen utilization. In our experiments, human breast cancer cells primarily assimilated ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH); secondary reactions enabled other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Metabolic recycling of ammonia accelerated proliferation of breast cancer. In mice, ammonia accumulated in the tumor microenvironment and was used directly to generate amino acids through GDH activity. These data show that ammonia is not only a secreted waste product but also a fundamental nitrogen source that can support tumor biomass.
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Breast cancer cells can engage in reductive amination, and GDH activity supports ammonia incorporation and tumor growth in mouse models of breast cancer.
“Indeed, breast cancer cells can engage in reductive amination, and GDH activity supports ammonia incorporation and tumor growth in mouse models of breast cancer (128).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [128]
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- Authors
- Spinelli, J. B., Yoon, H., Ringel, A. E., Jeanfavre, S., Clish, C. B., & Haigis, M. C.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- Corresponding author
- Haigis, Marcia C.
- Venue
- Science
- Published
- 2017-11-17
- Volume
- 358
- Issue
- 6365
- Pages
- 941-946
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5748897
- OpenAlex
- W2760863179
- Cited by
- 468
- References
- 43
- Citations by year
- 2026: 37 · 2025: 54 · 2024: 57 · 2023: 63 · 2022: 62 · 2021: 66 · 2020: 46 · 2019: 42 · 2018: 34 · 2017: 5
- FWCI
- 11.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- NIH Office of the Director (award344323, R01CA213062)
- 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 › Molecular Biology › Cancer and biochemical research
- Keywords
- ammonia recycling, glutamate dehydrogenase, breast cancer, nitrogen metabolism, reductive amination, amino acid biosynthesis, tumor microenvironment, tumor cell proliferation, proline, aspartic acid
- MeSH terms
- Amination, Ammonia, Animals, Aspartic Acid, Breast Neoplasms, Female, Glutamate Dehydrogenase, Humans, Proline, RNA, Small Interfering, Cell Proliferation, Mice, Biocatalysis, Tumor Microenvironment, MCF-7 Cells
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