Low expressions of ASS1 and OTC in glioblastoma suggest the potential clinical use of recombinant human arginase (rhArg)

Choy, Chi Tung; Wong, Chi Lok; Loong, Herbert H.

doi:10.1007/s11060-016-2209-7

Cited by 6 publications

(4 citation statements)

References 3 publications

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“…Recently, a key enzyme, ASS1, which can convert citrulline to arginine in the urea cycle, was found to have a frequent low expression in several types of tumors 6,7 . Choy 17 reported that a low expression of ASS1 in glioblastoma had the potential to be a predictive marker for therapeutic efficacy. Qiu 6 found that ASS1 was either low or absent in more than 60% breast cancer bio-samples.…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor regulates ASS1P3/miR-34a-5p/ASS1 signaling to promote renal cell carcinoma cell growth

et al. 2019

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Recent studies have demonstrated that the androgen receptor (AR) could play important roles to promote renal cell carcinoma (RCC) cell proliferation, and other studies have also indicated that suppressing the argininosuccinate synthase 1 (ASS1) could promote proliferation of various tumors. The potential of AR promoting cell proliferation in RCC via altering ASS1, however, remains unclear. Here we found that the expression of ASS1 was lower in RCC tissues than in adjacent normal renal tissues, and a lower ASS1 expression was linked to a worse prognosis in RCC patients. Mechanism dissection showed that AR could decrease ASS1 expression to promote RCC cell proliferation via ASS1P3, a pseudogene of ASS1. The results of RIP assay and AGO2 assay revealed that AR could bind ASS1P3 to increase RCC cell proliferation via altering miR-34a-5p function, which could bind to the 3′UTR of ASS1 to suppress its protein expression. ASS1P3 could function as a miRNA decoy for miR-34a-5p to regulate ASS1 in RCC. Preclinical study also supports the in vitro data. Together, these results demonstrated that ASS1P3 could function as a competing endogenous RNA to suppress RCC cell progression, and targeting this newly identified AR-mediated ASS1P3/miR-34a-5p/ASS1 signaling might help in blocking proliferation.

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Section: Discussionmentioning

confidence: 99%

Androgen receptor regulates ASS1P3/miR-34a-5p/ASS1 signaling to promote renal cell carcinoma cell growth

et al. 2019

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“…Many tumors show deficient expression of OTC and some other urea cycle enzymes. These comprise for example subpopulations of colorectal and hepatocellular carcinoma (Alexandrou et al, 2018;He et al, 2019), glioblastoma (Khoury et al, 2015;Choy et al, 2016), and pediatric sarcomas and brain tumors (Vardon et al, 2017). Such metabolic reprogramming would also lead to higher dependency on exogenous arginine supply, which suggests that arginine deprivation therapy could be a viable therapeutic approach for these tumors (Khoury et al, 2015;Vardon et al, 2017;Alexandrou et al, 2018).…”

Section: Otc: An Emerging Role In Chronic Disease?mentioning

confidence: 99%

Ornithine Transcarbamylase – From Structure to Metabolism: An Update

et al. 2021

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Ornithine transcarbamylase (OTC; EC 2.1.3.3) is a ubiquitous enzyme found in almost all organisms, including vertebrates, microorganisms, and plants. Anabolic, mostly trimeric OTCs catalyze the production of L-citrulline from L-ornithine which is a part of the urea cycle. In eukaryotes, such OTC localizes to the mitochondrial matrix, partially bound to the mitochondrial inner membrane and part of channeling multi-enzyme assemblies. In mammals, mainly two organs express OTC: the liver, where it is an integral part of the urea cycle, and the intestine, where it synthesizes citrulline for export and plays a major role in amino acid homeostasis, particularly of L-glutamine and L-arginine. Here, we give an overview on OTC genes and proteins, their tissue distribution, regulation, and physiological function, emphasizing the importance of OTC and urea cycle enzymes for metabolic regulation in human health and disease. Finally, we summarize the current knowledge of OTC deficiency, a rare X-linked human genetic disorder, and its emerging role in various chronic pathologies.

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“…Due to NBS, an increasing number of neonates with elevated citrulline levels of uncertain clinical significance are being identified. Analysis of the ASS1 gene can be used to confirm CTLN1 and, increasingly, to infer phenotypic severity (CHOY et al, 2016). The mutation c.1168G>A (p.Gly390Arg) in exon 15 accounts for up to 62% of alleles in European patients diagnosed with the disorder, and it is, therefore, the most common mutation in the classic form (DIEZ-FERNANDEZ et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Functional identification of two novel variants and a hypomorphic variant in ASS1 from patients with Citrullinemia type I

et al. 2023

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Background: Citrullinemia type I (CTLN1) is a rare autosomal recessive inborn error of the urea cycle caused by mutations in the gene encoding the arginosuccinate synthetase (ASS1) enzyme. Classic CTLN1 often manifests with acute hyperammonemia and neurological symptoms. Molecular genetic testing is critical for patient diagnosis.Methods: Three unrelated families with clinically suspected CTLN1 were included in this study. Potential pathogenic variants were identified using whole exome sequencing (WES) and validated using Sanger sequencing. Western blotting, quantitative PCR, immunofluorescent staining, and ELISA were used to assess functional changes in candidate ASS1 variants.Results: Five variants were identified, two of which were novel, and one has been reported, but its pathogenicity was not validated. The novel variant c.649-651del (p.P217del) and the 5′UTR variant (c.-4C>T) resulted in a decrease in ASS1 expression at both the protein and transcription levels. The other novel variant, c.1048C>T (p.Q350*), showed a marked decrease in expression at the protein level, with the formation of truncated proteins but an increased transcription. Both c.649_651del (p.P217del) and c.1048C>T (p.Q350*) showed a highly significant reduction in enzyme activity, while c.-4C>T had no effect.Conclusion: We identified two novel variants and a hypomorphic non-coding variant in ASS1 and validated the pathogenicity using functional studies. Our findings contribute to expanding the spectrum of ASS1 variants and understanding the genotype-phenotype relationships of CTLN1.

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Low expressions of ASS1 and OTC in glioblastoma suggest the potential clinical use of recombinant human arginase (rhArg)

Cited by 6 publications

References 3 publications

Androgen receptor regulates ASS1P3/miR-34a-5p/ASS1 signaling to promote renal cell carcinoma cell growth

Androgen receptor regulates ASS1P3/miR-34a-5p/ASS1 signaling to promote renal cell carcinoma cell growth

Ornithine Transcarbamylase – From Structure to Metabolism: An Update

Functional identification of two novel variants and a hypomorphic variant in ASS1 from patients with Citrullinemia type I

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