Publication Date:
2015-11-13
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655447/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655447/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- 1 U54 HD083092/HD/NICHD NIH HHS/ -- England -- Nature. 2015 Nov 19;527(7578):379-83. doi: 10.1038/nature15529. Epub 2015 Nov 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel. ; The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel. ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Biological Services, Weizmann Institute of Science, Rehovot 69978, Israel. ; Human and Molecular Genetic and Biochemistry Center, Medical College Wisconsin, Milwaukee, Wisconsin 53226, USA. ; Genetic and Metabolic Center, Hadassah Medical Center, Jerusalem 91120, Israel. ; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 69978, Israel. ; Texas Children's Hospital, Houston, Texas 77030, USA. ; The Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. ; Center for Bioinformatics and Computational Biology &Department of Computer Science, University of Maryland, College Park, Maryland 20742, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26560030" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Argininosuccinate Synthase/*deficiency/metabolism
;
Aspartate Carbamoyltransferase/metabolism
;
Aspartic Acid/*metabolism
;
Calcium-Binding Proteins/antagonists & inhibitors/metabolism
;
Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)/metabolism
;
Cell Line, Tumor
;
Cell Proliferation
;
Citrullinemia/metabolism
;
Cytosol/metabolism
;
Dihydroorotase/metabolism
;
Down-Regulation
;
Enzyme Activation
;
Humans
;
Male
;
Mice
;
Mice, SCID
;
Neoplasms/enzymology/*metabolism/pathology
;
Organic Anion Transporters/antagonists & inhibitors/metabolism
;
Phosphorylation
;
Pyrimidines/*biosynthesis
;
TOR Serine-Threonine Kinases/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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