Loss of Carbamoyl Phosphate Synthetase 1 Potentiates Hepatocellular Carcinoma Metastasis by Reducing Aspartate Level
Abstract Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Numerous studies have shown that metabolic reprogramming is crucial for the development of HCC. Carbamoyl phosphate synthase 1 (CPS1), a rate‐limiting enzyme in urea cycle, is an abundant protein in normal hepatocyt...
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202402703 |
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| author | Siyuan Chen Qin Tang Manqiu Hu Sijie Song Xiaohong Wu You Zhou Zihan Yang Siqi Liao Li Zhou Qingliang Wang Hongtao Liu Mengsu Yang Zhe‐Sheng Chen Wei Zhao Song He Zhihang Zhou |
| author_facet | Siyuan Chen Qin Tang Manqiu Hu Sijie Song Xiaohong Wu You Zhou Zihan Yang Siqi Liao Li Zhou Qingliang Wang Hongtao Liu Mengsu Yang Zhe‐Sheng Chen Wei Zhao Song He Zhihang Zhou |
| author_sort | Siyuan Chen |
| collection | DOAJ |
| description | Abstract Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Numerous studies have shown that metabolic reprogramming is crucial for the development of HCC. Carbamoyl phosphate synthase 1 (CPS1), a rate‐limiting enzyme in urea cycle, is an abundant protein in normal hepatocytes, however, lacking systemic research in HCC. It is found that CPS1 is low‐expressed in HCC tissues and circulating tumor cells, negatively correlated with HCC stage and prognosis. Further study reveals that CPS1 is a double‐edged sword. On the one hand, it inhibits the activity of phosphatidylcholine‐specific phospholipase C to block the biosynthesis of diacylglycerol (DAG), leading to the downregulation of the DAG/protein kinase C pathway to inhibit invasion and metastasis of cancer cells. On the other hand, CPS1 promotes cell proliferation by increasing intracellular S‐adenosylmethionin to enhance the m6A modification of solute carrier family 1 member 3 mRNA, a key transporter for aspartate intake. Finally, CPS1 overexpressing adeno‐associated virus can dampen HCC progression. Collectively, this results uncovered that CPS1 is a switch between HCC proliferation and metastasis by increasing intracellular aspartate level. |
| format | Article |
| id | doaj-art-2e8952e540a94e2fa9db65bef10c5b9d |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-2e8952e540a94e2fa9db65bef10c5b9d2024-12-04T12:14:54ZengWileyAdvanced Science2198-38442024-12-011145n/an/a10.1002/advs.202402703Loss of Carbamoyl Phosphate Synthetase 1 Potentiates Hepatocellular Carcinoma Metastasis by Reducing Aspartate LevelSiyuan Chen0Qin Tang1Manqiu Hu2Sijie Song3Xiaohong Wu4You Zhou5Zihan Yang6Siqi Liao7Li Zhou8Qingliang Wang9Hongtao Liu10Mengsu Yang11Zhe‐Sheng Chen12Wei Zhao13Song He14Zhihang Zhou15Department of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Biomedical Sciences and Tung Biomedical Sciences Center City University of Hong Kong 83 Tat Chee Avenue Kowloon Hong Kong SAR 999077 P. R. ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Pathology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Biomedical Sciences and Tung Biomedical Sciences Center City University of Hong Kong 83 Tat Chee Avenue Kowloon Hong Kong SAR 999077 P. R. ChinaDepartment of Pharmaceutical Sciences Institute for Biotechnology College of Pharmacy and Health Sciences St. John's University Queens NY 11439 USASchool of Clinical Medicine The First Affiliated Hospital Chengdu Medical College Sichuan 610500 P. R. ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaAbstract Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Numerous studies have shown that metabolic reprogramming is crucial for the development of HCC. Carbamoyl phosphate synthase 1 (CPS1), a rate‐limiting enzyme in urea cycle, is an abundant protein in normal hepatocytes, however, lacking systemic research in HCC. It is found that CPS1 is low‐expressed in HCC tissues and circulating tumor cells, negatively correlated with HCC stage and prognosis. Further study reveals that CPS1 is a double‐edged sword. On the one hand, it inhibits the activity of phosphatidylcholine‐specific phospholipase C to block the biosynthesis of diacylglycerol (DAG), leading to the downregulation of the DAG/protein kinase C pathway to inhibit invasion and metastasis of cancer cells. On the other hand, CPS1 promotes cell proliferation by increasing intracellular S‐adenosylmethionin to enhance the m6A modification of solute carrier family 1 member 3 mRNA, a key transporter for aspartate intake. Finally, CPS1 overexpressing adeno‐associated virus can dampen HCC progression. Collectively, this results uncovered that CPS1 is a switch between HCC proliferation and metastasis by increasing intracellular aspartate level.https://doi.org/10.1002/advs.202402703aspartateCPS1m6AmetastasisPC‐PLC |
| spellingShingle | Siyuan Chen Qin Tang Manqiu Hu Sijie Song Xiaohong Wu You Zhou Zihan Yang Siqi Liao Li Zhou Qingliang Wang Hongtao Liu Mengsu Yang Zhe‐Sheng Chen Wei Zhao Song He Zhihang Zhou Loss of Carbamoyl Phosphate Synthetase 1 Potentiates Hepatocellular Carcinoma Metastasis by Reducing Aspartate Level Advanced Science aspartate CPS1 m6A metastasis PC‐PLC |
| title | Loss of Carbamoyl Phosphate Synthetase 1 Potentiates Hepatocellular Carcinoma Metastasis by Reducing Aspartate Level |
| title_full | Loss of Carbamoyl Phosphate Synthetase 1 Potentiates Hepatocellular Carcinoma Metastasis by Reducing Aspartate Level |
| title_fullStr | Loss of Carbamoyl Phosphate Synthetase 1 Potentiates Hepatocellular Carcinoma Metastasis by Reducing Aspartate Level |
| title_full_unstemmed | Loss of Carbamoyl Phosphate Synthetase 1 Potentiates Hepatocellular Carcinoma Metastasis by Reducing Aspartate Level |
| title_short | Loss of Carbamoyl Phosphate Synthetase 1 Potentiates Hepatocellular Carcinoma Metastasis by Reducing Aspartate Level |
| title_sort | loss of carbamoyl phosphate synthetase 1 potentiates hepatocellular carcinoma metastasis by reducing aspartate level |
| topic | aspartate CPS1 m6A metastasis PC‐PLC |
| url | https://doi.org/10.1002/advs.202402703 |
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