2. Academic Validation
  3. Loss of Carbamoyl Phosphate Synthetase 1 Potentiates Hepatocellular Carcinoma Metastasis by Reducing Aspartate Level

Loss of Carbamoyl Phosphate Synthetase 1 Potentiates Hepatocellular Carcinoma Metastasis by Reducing Aspartate Level

  • Adv Sci (Weinh). 2024 Oct 10:e2402703. doi: 10.1002/advs.202402703.
Siyuan Chen 1,  Qin Tang 1,  Manqiu Hu 1,  Sijie Song 1,  Xiaohong Wu 1,  You Zhou 1,  Zihan Yang 2,  Siqi Liao 1,  Li Zhou 1,  Qingliang Wang 3,  Hongtao Liu 1,  Mengsu Yang 2,  Zhe-Sheng Chen 4,  Wei Zhao 5 6,  Song He 1,  Zhihang Zhou 1
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
  • 2 Department of Biomedical Sciences, and Tung Biomedical Sciences Center, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong SAR, 999077, P. R. China.
  • 3 Department of Pathology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
  • 4 Department of Pharmaceutical Sciences, Institute for Biotechnology, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
  • 5 School of Clinical Medicine, The First Affiliated Hospital, Chengdu Medical College, Sichuan, 610500, P. R. China.
  • 6 Department of Clinical Biochemistry, School of Laboratory Medicine, Chengdu Medical College, Sichuan, 610500, P. R. China.
PMID: 39387452 DOI: 10.1002/advs.202402703
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.

Keywords

CPS1; PC‐PLC; aspartate; m6A; metastasis.

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