Journal
NATURE
Volume 527, Issue 7578, Pages 379-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature15529
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Categories
Funding
- Weizmann Institute
- European Research Program [CIG618113, ERC614204]
- Israel Science Foundation [1343/13, 1952/13]
- Minerva grant award [711730]
- Adelis Foundation
- Henry S. and Anne S. Reich Research Fund
- Dukler Fund for Cancer Research
- Paul Sparr Foundation
- Saul and Theresa Esman Foundation
- estate of Fannie Sherr
- Teva
- Israeli Science Foundation [41/11]
- Israeli Cancer Research Fund
- Israeli Center of Excellence (I-CORE) Program of the Planning and Budgeting Committee
- Israel Cancer Research Foundation
- Baylor College of Medicine Intellectual and Developmental Disabilities Research Center Grant from the Eunice Kennedy Shriver National Institute of Child Health & Human Development [1 U54 HD083092]
- Doris Duke Charitable Foundation [DDCF 2013095]
- Rising Tide Foundation
- Abramson Family Center for Young Scientists
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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(1). 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(2). 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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