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Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis
Open accessAbstract
Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate synthase (ASS1) is a urea cycle enzyme that is essential in the conversion of nitrogen from ammonia and aspartate to urea. A decrease in nitrogen flux through ASS1 in the liver causes the urea cycle disorder citrullinaemia. In contrast to the well-studied consequences of loss of ASS1 activity on ureagenesis, the purpose of its somatic silencing in multiple cancers is largely unknown. Here we show that decreased activity of ASS1 in cancers supports proliferation by facilitating pyrimidine synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation. Our studies were initiated by delineating the consequences of loss of ASS1 activity in humans with two types of citrullinaemia. We find that in citrullinaemia type I (CTLN I), which is caused by deficiency of ASS1, there is increased pyrimidine synthesis and proliferation compared with citrullinaemia type II (CTLN II), in which there is decreased substrate availability for ASS1 caused by deficiency of the aspartate transporter citrin. Building on these results, we demonstrate that ASS1 deficiency in cancer increases cytosolic aspartate levels, which increases CAD activation by upregulating its substrate availability and by increasing its phosphorylation by S6K1 through the mammalian target of rapamycin (mTOR) pathway. Decreasing CAD activity by blocking citrin, the mTOR signalling, or pyrimidine synthesis decreases proliferation and thus may serve as a therapeutic strategy in multiple cancers where ASS1 is downregulated. Our results demonstrate that ASS1 downregulation is a novel mechanism supporting cancerous proliferation, and they provide a metabolic link between the urea cycle enzymes and pyrimidine synthesis.
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“Genetic or epigenetic silencing of ASS1 expression provides an advantage to tumor cells by allowing them to preserve cellular aspartate (Rabinovich et al., 2015), a poorly transported nutrient that can be a critical output of the TCA cycle to support de novo nucleotide synthesis and cell proliferation (Birsoy et al., 2015; Sullivan et al., 2015).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Rabinovich et al., 2015
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Caldovic, L., Ahn, J. J., Andricovic, J., Balick, V., Brayer, M., Chansky, P. A., Dawson, T., Edwards, A. C., Felsen, S. E., Ismat, K., et al. (2023) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12687 · Cited by 4
Transcriptome analysis of anaerobic glycolysis effects on Jurkat T cell proliferation
Wang, Z., Wang, H., Wang, Q., Huang, T., Guo, C., Ji, J., Su, M., Xu, W., Cao, Y., & Dong, Z. (2024) · Central European Journal of Immunology · doi:10.5114/ceji.2024.142116 · Cited by 4
Gupta, A., Choueiry, F., Reardon, J. J., Pramod, N., Kulkarni, A., Shankar, E., Sizemore, S. T., Stover, D. G., Zhu, J., Ramaswamy, B., et al. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07788-6 · Cited by 4
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Zhang, Z., Liu, X., Wu, Q., Liang, J., Zhao, Y., Deng, J., Wang, Y., Yu, Q., Ye, Z., Zhu, H., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-27576-8 · Cited by 4
Nagel, R., Kochavi, A., Karlsen, K. F., Adhikary, M., Gal-On, Y., Klaoudatou, M. G., Champagne, J., Valcanover, L., Palashati, H., Nielsen, M. M., et al. (2026) · Cancer Research · doi:10.1158/0008-5472.can-25-4773 · Cited by 4
Zhu, X., Guo, M., Ni, L., Chang, D., Wang, W., Xu, X., Liu, X., Yang, J., & Li, Z. (2026) · Genomics · doi:10.1016/j.ygeno.2026.111272 · Cited by 5
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Metadata
- Authors
- Rabinovich, S., Adler, L., Yizhak, K., Sarver, A., Silberman, A., Agron, S., Stettner, N., Sun, Q., Brandis, A., Helbling, D., Korman, S., Itzkovitz, S., Dimmock, D., Ulitsky, I., Nagamani, S. C. S., Ruppin, E., & Erez, A.
- Affiliations
- Weizmann Institute of Science (IL)
- Tel Aviv University (IL)
- Baylor College of Medicine (US)
- Medical College of Wisconsin (US)
- Hadassah Medical Center (IL)
- Corresponding author
- Erez, Ayelet
- ORCID
- Venue
- Nature
- Published
- 2015-11
- Volume
- 527
- Issue
- 7578
- Pages
- 379-383
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4655447
- OpenAlex
- W2129920232
- Cited by
- 382
- References
- 26
- Citations by year
- 2026: 31 · 2025: 45 · 2024: 34 · 2023: 38 · 2022: 48 · 2021: 58 · 2020: 30 · 2019: 32 · 2018: 30 · 2017: 19 · 2016: 15 · 2015: 1
- FWCI
- 9.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Doris Duke Charitable Foundation (2013095)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083092)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- argininosuccinate synthetase, aspartate transcarbamylase, dihydroorotase, pyrimidine synthesis, urea cycle, citrullinemia, citrin, aspartic acid, mTOR signaling, S6K1, tumor cell proliferation, metabolic reprogramming, citrulline
- MeSH terms
- Animals, Argininosuccinate Synthase, Aspartate Carbamoyltransferase, Aspartic Acid, Calcium-Binding Proteins, Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing), Cytosol, Dihydroorotase, Enzyme Activation, Humans, Male, Neoplasms, Phosphorylation, Pyrimidines, Down-Regulation, Mice, SCID, Citrullinemia, Organic Anion Transporters, Cell Line, Tumor, Cell Proliferation, Mice, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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