Cited by 382Biochemical and Molecular ResearchAmino Acid Enzymes and MetabolismCancer, Hypoxia, and Metabolism

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Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis

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Rabinovich, Shiran, Adler, Lital, Yizhak, Keren, Sarver, Alona, Silberman, Alon, Agron, Shani, Stettner, Noa, Sun, Qin, Brandis, Alexander, Helbling, Daniel, Korman, Stanley, Itzkovitz, Shalev, Dimmock, David, Ulitsky, Igor, Nagamani, Sandesh C. S., Ruppin, Eytan, Erez, Ayelet·2015·Nature

DOI 10.1038/nature15529PMC PMC4655447

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Abstract

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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(2024) · eLife · doi:10.7554/elife.96783.1.sa1
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(2024) · eLife · doi:10.7554/elife.96783.1.sa0
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Additional file 5 of Intracellular arginine-dependent translation sensor reveals the dynamics of arginine starvation response and resistance in ASS1-negative cells
Rogers, L. C., Zhou, J., Baker, A., Schutt, C. R., Panda, P. K., & Van Tine, B. A. (2021) · Figshare · doi:10.6084/m9.figshare.13627465
Additional file 1 of Intracellular arginine-dependent translation sensor reveals the dynamics of arginine starvation response and resistance in ASS1-negative cells
Rogers, L. C., Zhou, J., Baker, A., Schutt, C. R., Panda, P. K., & Van Tine, B. A. (2021) · Figshare · doi:10.6084/m9.figshare.13627453
Additional file 4 of Intracellular arginine-dependent translation sensor reveals the dynamics of arginine starvation response and resistance in ASS1-negative cells
Rogers, L. C., Zhou, J., Baker, A., Schutt, C. R., Panda, P. K., & Van Tine, B. A. (2021) · Figshare · doi:10.6084/m9.figshare.13627462
Additional file 2 of Intracellular arginine-dependent translation sensor reveals the dynamics of arginine starvation response and resistance in ASS1-negative cells
Rogers, L. C., Zhou, J., Baker, A., Schutt, C. R., Panda, P. K., & Van Tine, B. A. (2021) · Figshare · doi:10.6084/m9.figshare.13627456
Additional file 7 of Intracellular arginine-dependent translation sensor reveals the dynamics of arginine starvation response and resistance in ASS1-negative cells
Rogers, L. C., Zhou, J., Baker, A., Schutt, C. R., Panda, P. K., & Van Tine, B. A. (2021) · Figshare · doi:10.6084/m9.figshare.13627471
Additional file 6 of Intracellular arginine-dependent translation sensor reveals the dynamics of arginine starvation response and resistance in ASS1-negative cells
Rogers, L. C., Zhou, J., Baker, A., Schutt, C. R., Panda, P. K., & Van Tine, B. A. (2021) · Figshare · doi:10.6084/m9.figshare.13627468
Additional file 3 of Intracellular arginine-dependent translation sensor reveals the dynamics of arginine starvation response and resistance in ASS1-negative cells
Rogers, L. C., Zhou, J., Baker, A., Schutt, C. R., Panda, P. K., & Van Tine, B. A. (2021) · Figshare · doi:10.6084/m9.figshare.13627459
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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: Adler, Lital
Yizhak, Keren
Agron, Shani
Stettner, Noa
Sun, Qin
Brandis, Alexander
Helbling, Daniel
Itzkovitz, Shalev
Dimmock, David
Ulitsky, Igor
Nagamani, Sandesh C. S.
Ruppin, Eytan
Erez, Ayelet
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2015-11
Volume: 527
Issue: 7578
Pages: 379-383
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature15529
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

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Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis

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