<p>Exploring Metabolic Consequences of<em> CPS1</em> and<em> CAD</em> Dysregulation in Hepatocellular Carcinoma by Network Reconstruction</p>

Abstract

Purpose: Hepatocellular carcinoma (HCC) is the fourth commonest cause of cancer-related mortality; it is associated with various genetic alterations, some involved in metabolic reprogramming. This study aimed to explore the potential metabolic impact of Carbamoyl Phosphate Synthase I (CPS1) and carbamoyl phosphate synthetase/aspartate transcarbamoylase/dihydroorotase (CAD) dysregulation through the reconstruction of a network that integrates information from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, Human Metabolome Database (HMDB) and Human Protein Atlas (HPA). Methods and results: Existing literature was used to determine the roles of CPS1 and CAD in HCC. CPS1 downregulation is thought to play a role in hepatocarcinogenesis through an increased glutamine availability for de novo pyrimidine biosynthesis, which CAD catalyzes the first three steps for. KEGG, HMDB and HPA were used to reconstruct a network of relevant pathways, demonstrating the relationships between genes and metabolites using the MetaboSignal package in R. The network was filtered to exclude any duplicates, and those greater than three steps away from CPS1 or CAD. Consequently, a network of 18 metabolites, 28 metabolic genes and 1 signaling gene was obtained, which indicated expression profiles and prognostic information of each gene in the network. Conclusion: Information from different databases was collated to form an informative network that integrated different "-omics" approaches, demonstrating the relationships between genetic and metabolic components of urea cycle and the de novo pyrimidine biosynthesis pathway. This study paves the way for further research by acting as a template to investigate the relationships between genes and metabolites, explore their potential roles in various diseases and aid the development of new screening and treatment methods through network reconstruction.

Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma

“…Besides, the design of metabolic targeted therapeutic strategies should also evaluate the tumor heterogeneity and interaction with the micro-environment carefully, giving rise to the difficulties in development of effective drugs. Therefore, the exploration of new agents, especially traditional Chinese medicine monomers, such as genistein, 15d-PGJ2, quercetin, and oleanolic acid, to test for antiglycolysis effects are urgently needed with the help of proteomics and metabolomics analyses and genomescale metabolic models [26,[187][188][189][190].…”

Key enzymes in pyrimidine synthesis, CAD and CPS1, predict prognosis in hepatocellular carcinoma

“…Macrovascular invasion, one of the most significant predictors of early HCC recurrence, was associated with a downregulation of different UC enzymes, including CPS1 [16]. A reduction in CPS1 in HCC may result in increased shunting of glutamine to CAD, which is the initiating step of the de novo pyrimidine synthesis pathway, and may lead to unfavorable outcomes [17]. In order to elucidate the role of CAD and CPS1 and their effect on prognosis in HCC, we investigated the expression of both enzymes in a large collective of HCCs in comparison to respective non-neoplastic liver tissue by immunohistochemistry and correlated their expression with clinical and histopathological features.…”

Inhibition of the urea cycle by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin increases serum ammonia levels in mice

“…Carbamoyl phosphate can also be generated by carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase, a trifunctional protein involved in pyrimidine synthesis but not evaluated. Interestingly, isoform switching between CPS1 and CPSII ( via carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) occurs in hepatocellular carcinoma (HCC) to support pyrimidine synthesis and cell proliferation ( 72 ). Similarly, TCDD, a known hepatocarcinogen in rodents, induces PKM isoform switching ( 33 ), a biochemical phenomenon linked to the Warburg effect in cancerous cells as a mechanism to anabolic processes and cell division ( 73 ).…”