ArticleBMC cancer2014
Down-regulation of argininosuccinate synthetase is associated with cisplatin resistance in hepatocellular carcinoma cell lines: implications for PEGylated arginine deiminase combination therapy.
Article in BMC cancer, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 63 citations in OpenAlex.
- Trial
- Arginine Deprivation of ASS1-Deficient Cancers Drives Mistranslation and Shared Neoepitope Production.Cancer research · 2026Article
- Targeting arginine metabolism overcomes chemotherapy resistance in aggressive-variant prostate cancers.iScience · 2026Article
- Impaired nitrogenous waste clearance promotes hepatocellular carcinoma.Science advances · 2026Article
- Evodiamine Inhibits Colorectal Cancer by Downregulating ASS1 via Wnt/β-Catenin/c-MYC Pathway to Block Arginine Synthesis.Pharmaceuticals (Basel, Switzerland) · 2025Article
- mAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Molecular network of metabolic reprogramming and precision diagnosis and treatment of hepatocellular carcinoma.Biomarker research · 2025Review
- Synergistic effects of L-arginine and argininosuccinate synthetase 1 in inducing apoptosis in hepatocellular carcinoma.Journal of liver cancer · 2025Article
- Metabolic reprogramming in hepatocellular carcinoma: mechanisms and therapeutic implications.Experimental & molecular medicine · 2025Review
- From the Inside Out: Exposing the Roles of Urea Cycle Enzymes in Tumors and Their Micro and Macro Environments.Cold Spring Harbor perspectives in medicine · 2024Review
- Unlocking the Potential of Arginine Deprivation Therapy: Recent Breakthroughs and Promising Future for Cancer Treatment.International journal of molecular sciences · 2023Review
- A pan-cancer analysis of the role of argininosuccinate synthase 1 in human tumors.Frontiers in oncology · 2023Article
- Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression.Nature communications · 2022Article
- In silico and in vitro analysis of arginine deiminase from3 Biotech · 2022Article
- Pegylated arginine deiminase drives arginine turnover and systemic autophagy to dictate energy metabolism.Cell reports. Medicine · 2022Article
- Phase 1 trial of ADI-PEG 20 and liposomal doxorubicin in patients with metastatic solid tumors.Cancer medicine · 2022Article
- Metabolic reprogramming in renal cancer: Events of a metabolic disease.Biochimica et biophysica acta. Reviews on cancer · 2021Review
- Metabolic Strategies for Inhibiting Cancer Development.Advances in nutrition (Bethesda, Md.) · 2021Review
- Arginine Signaling and Cancer Metabolism.Cancers · 2021Review
- Cytosolic Delivery of Argininosuccinate Synthetase Using a Cell-Permeant Miniature Protein.ACS central science · 2021Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMany advanced human tumors, including hepatocellular carcinomas (HCC) are auxotrophic for arginine due to down-regulation of argininosuccinate synthetase (ASS1), the rate-limiting enzyme in arginine synthesis. The arginine-lowering agent PEGylated arginine deiminase (ADI-PEG 20) has shown efficacy as a monotherapy in clinical trials for treating arginine-auxotrophic tumors and is currently being evaluated in combination with cisplatin in other cancer types. Epigenetic silencing via methylation of the ASS1 promoter has been previously demonstrated in other cancer types, and a reciprocal relationship between ASS1 expression and cisplatin resistance has also been observed in ovarian cancer. However, the mechanism of ASS1 down-regulation, as well as the correlation with cisplatin resistance has not been explored in HCC. The present study investigates ADI-PEG 20 and cisplatin sensitivities in relation to ASS1 expression in HCC. In addition, we show how this biomarker is regulated by cisplatin alone and in combination with ADI-PEG 20.
methodsASS1 protein expression in both untreated and drug treated human HCC cell lines was assessed by western blot. The correlation between ASS1 protein levels, ADI-PEG 20 sensitivity and cisplatin resistance in these cell lines was established using a luminescence-based cell viability assay. Epigenetic regulation of ASS1 was analyzed by bisulfite conversion and methylation-specific PCR.
resultsA good correlation between absence of ASS1 protein expression, ASS1 promoter methylation, sensitivity to ADI-PEG 20 and resistance to cisplatin in HCC cell lines was observed. In addition, cisplatin treatment down-regulated ASS1 protein expression in select HCC cell lines. While, at clinically relevant concentrations, the combination of ADI-PEG 20 and cisplatin restored ASS1 protein levels in most of the cell lines studied.
conclusionASS1 silencing in HCC cell lines is associated with simultaneous cisplatin resistance and ADI-PEG 20 sensitivity which suggests a promising combination therapeutic strategy for the management of HCC.
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