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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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The urea cycle is transcriptionally controlled by hypoxia-inducible factorsPreprint
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“Recently, recycling of ammonia has been shown to accelerate the proliferation rate of cancer cells (1, 2).”
BackgroundLittle, R. B. (2021) · viXra · Cited by 2
Extracellular Domains of CAR Reprogram T-Cell Metabolism Without Antigen StimulationPreprint
Lakhani, A., Chen, X., Chen, L. C., Khericha, M., Chen, Y. Y., & Park, J. O. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.03.533021 · Cited by 2
Study of the effects of quercetin on experimentally induced hepatic toxicity in rats
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Metabolic Flexibility: Targeting Mitochondrial Dynamics in Cancer Therapy
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“Tumors appear to co-opt tRNA modifications; the enhanced translation of GAG codon-enriched mRNAs via tRNA Glu-CTC m 1 A hypermethylation may reflect the metabolic demands of CRC [ 32 ].”
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Ammonia signaling network: the intersection of tumor metabolism, epigenetics, and metastasis
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“…have demonstrated that while cancer cells recycle low levels of ammonia to support biomass, the accumulation of ammonia beyond a critical threshold becomes lethal if the cells lack robust ammonia assimilation and clearance mechanisms, such as suf fi cient expression of glutamine synthetase (40).”
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Electron collision with Ammonia and phosphine at wide range of energies
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Volatile Organic Compounds (VOCs) and Interleukin-23 Levels in Lung Cancer: A Future Biomarker
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A reversible smartphone-based fluorescent probe for the rapid detection of ammonia in biofluids
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Carbohydrate and protein metabolism
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Metabolic Phenotyping in Clinical Practice
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Single-Cell Technologies for Cancer Therapy
Hu, G., Lee, V. D., Lin, H., Mao, P.-W., Liu, H., Peh, J.-H., & Chen, C. (2021) · Springer eBooks · doi:10.1007/978-981-10-8953-4_10 · Cited by 1
The Fate of Glutamine in Human Metabolism. The interplay with glucose in proliferating cellsPreprint
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“Complicating this atypical dissemination pattern, advanced or metastatic ILC may not be as easily detected by positron emission tomography using the glucose analog tracer 18 F-fluorodeoxyglucose (i.e. [ 18 F]FDG-PET) 4 , as several clinical studies have shown ILC has limited FDG avidity.”
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Single-Cell Technologies for Cancer Therapy
Hu, G., Lee, V. D., Lin, H., Mao, P.-W., Liu, H., Peh, J.-H., & Chen, C. (2019) · Springer eBooks · doi:10.1007/978-981-10-4857-9_10-1
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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