ArticleOncotarget2016
Cisplatin-induced synthetic lethality to arginine-starvation therapy by transcriptional suppression of ASS1 is regulated by DEC1, HIF-1α, and c-Myc transcription network and is independent of ASS1 promoter DNA methylation.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
38 citing papers in PubMed, 63 citations in OpenAlex.
- Trial
- Targeting arginine metabolism overcomes chemotherapy resistance in aggressive-variant prostate cancers.iScience · 2026Article
- Dynamic remodeling of amino acid metabolism in tumor-associated macrophages: Fueling immunosuppression, reshaping tumor niches, and unlocking metabolic checkpoints.Journal of advanced research · 2026Review
- Nitrogen Isotope Effects in Urea Metabolism: From Biochemistry toInternational journal of molecular sciences · 2026Review
- The role of L-Arginine metabolism in the hallmarks of cancer as an emerging pathway to drug design.Frontiers in pharmacology · 2026Review
- Decoding amino acid metabolism in hepatocellular carcinoma: critical nodes and novel therapeutic strategy.Frontiers in oncology · 2026Review
- Endothelial Arginine Metabolism in Angiogenesis: Mechanistic Insights from Tissue Repair to Tumor Progression.Metabolites · 2025Review
- Invasive lobular carcinoma: integrated multi-omics analysis reveals silencing of Argininosuccinate synthase and upregulation of nucleotide biosynthesis in tamoxifen resistance.Cell death & disease · 2025Article
- BCL-XL Protects ASS1-Deficient Cancers from Arginine Starvation-Induced Apoptosis.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Synergistic effects of L-arginine and argininosuccinate synthetase 1 in inducing apoptosis in hepatocellular carcinoma.Journal of liver cancer · 2025Article
- Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma.iScience · 2025Article
- Targeting the kynurenine pathway: another therapeutic opportunity in the metabolic crosstalk between cancer and immune cells.Frontiers in oncology · 2024Article
- Arginine depletion attenuates renal cystogenesis in tuberous sclerosis complex model.Cell reports. Medicine · 2023Article
- Bench-to-Bedside Studies of Arginine Deprivation in Cancer.Molecules (Basel, Switzerland) · 2023Review
- Plateau Adaptation Gene Analyses Reveal Transcriptomic, Proteomic, and Dual Omics Expression in the Lung Tissues of Tibetan and Yorkshire Pigs.Animals : an open access journal from MDPI · 2022Article
- Activation of VIPR1 suppresses hepatocellular carcinoma progression by regulating arginine and pyrimidine metabolism.International journal of biological sciences · 2022Article
- Hepatocyte-Specific Knock-Out of Nfib Aggravates Hepatocellular Tumorigenesis via Enhancing Urea Cycle.Frontiers in molecular biosciences · 2022Article
- Epithelial argininosuccinate synthetase is dispensable for intestinal regeneration and tumorigenesis.Cell death & disease · 2021Article
- Snail enhances arginine synthesis by inhibiting ubiquitination-mediated degradation of ASS1.EMBO reports · 2021Article
- Enhancing the Effect of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Signaling and Arginine Deprivation in Melanoma.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
Abstract
Many human tumors require extracellular arginine (Arg) for growth because the key enzyme for de novo biosynthesis of Arg, argininosuccinate synthetase 1 (ASS1), is silenced. These tumors are sensitive to Arg-starvation therapy using pegylated arginine deiminase (ADI-PEG20) which digests extracellular Arg. Many previous studies reported that ASS1 silencing is due to epigenetic inactivation of ASS1 expression by DNA methylation, and that the demethylation agent 5-aza-deoxycytidine (Aza-dC) can induce ASS1 expression. Moreover, it was reported that cisplatin suppresses ASS1 expression through ASS1 promoter methylation, leading to synthetic lethality to ADI-PEG20 treatment. We report here that cisplatin supppresses ASS1 expression is due to upregulation of HIF-1α and downregulation of c-Myc, which function as negative and positive regulators of ASS1 expression, respectively, by reciprocal bindings to the ASS1 promoter. In contrast, we found that Aza-dC induces ASS1 expression by downregulation of HIF-1α but upregulation of c-Myc. We further demonstrated that the clock protein DEC1 is the master regulator of HIF-1α and c-Myc that regulate ASS1. cDDP upregulates DEC1, whereas Aza-dC suppresses its expression. Using two proteasomal inhibitors bortezomib and carfilzomib which induce HIF-1α accumulation, we further demonstrated that HIF-1α is involved in ASS1 silencing for the maintenance of Arg auxotrophy for targeted Arg-starvation therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.