The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index.
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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“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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Cites
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“However, in the tumor microenvironment, metabolic waste such as lactate and ammonia accumulate (4, 5).”
BackgroundThe emerging hallmarks of cancer metabolism
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“contradicted in catabolic glutamine metabolism, because nitrogen is liberated as the byproduct ammonia (11).”
BackgroundFrom Krebs to clinic: glutamine metabolism to cancer therapy
Altman, B. J., Stine, Z. E., & Dang, C. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.71 · Cited by 2,119 · cited 2×
“Glutamine has been called a “nitrogen reservoir” for cancer cells because of its anabolic role in nucleotide synthesis (6, 10).”
BackgroundVyas, S., Zaganjor, E., & Haigis, M. C. (2016) · Cell · doi:10.1016/j.cell.2016.07.002 · Cited by 1,735
Analysis of apoptosis by propidium iodide staining and flow cytometry
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Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer
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Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells
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- 10.1016/0006-291X(90)90660-F · DOI
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The multifaceted contributions of mitochondria to cellular metabolism
Spinelli, J. B., & Haigis, M. C. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0124-1 · Cited by 1,935
The hallmarks of cancer metabolism: still emerging
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Targeting p53 pathways: mechanisms, structures, and advances in therapy
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“Tumor cells produce large amounts of ammonia during amino acid metabolism, and this ammonia can serve as a nitrogen source for tumor growth.(108,109) p53 regulates ammonia content in tumor cells through the urea cycle.”
BackgroundMetabolites and the Tumour Microenvironment: From Cellular Mechanisms to Systemic Metabolism
Elia, I., & Haigis, M. C. (2021) · Nature Metabolism · doi:10.1038/s42255-020-00317-z · Cited by 651
Metabolic modulation of tumours with engineered bacteria for immunotherapy
Canale, F. P., Basso, C., Antonini, G., Perotti, M., Li, N., Sokolovska, A., Neumann, J., James, M. J., Geiger, S., Jin, W., et al. (2021) · Nature · doi:10.1038/s41586-021-04003-2 · Cited by 619
Metadata
- 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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