ArticleCancer research2019
Acid-Induced Downregulation of ASS1 Contributes to the Maintenance of Intracellular pH in Cancer.
Article in Cancer research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 60 citations in OpenAlex.
- Comprehensive molecular characterization of cfDNA as predictive and monitoring biomarkers in advanced gastric cancer receiving immunotherapy.Journal for immunotherapy of cancer · 2026Article
- The role of L-Arginine metabolism in the hallmarks of cancer as an emerging pathway to drug design.Frontiers in pharmacology · 2026Review
- Sustained hypoxia induces divergent response patterns in cardiac metabolic-immune adaptation and circadian rhythm regulation.PloS one · 2026Article
- Ammonia in cancer: dual roles and therapeutic strategies.Cancer cell international · 2025Review
- Targeting AQP5-mediated arginine deprivation in gastric cancer stem cells restores NK cell anti-tumor immunity.Cell reports. Medicine · 2025Article
- Integrated multi‑omics analysis of liver metabolic dysregulation in ACE2 knockout mice.International journal of molecular medicine · 2025Article
- Novel roles of ammonia in physiology and cancer.Journal of molecular cell biology · 2025Review
- Etoposide-induced protein 2.4 homolog promotes argininosuccinate synthase 1 and cancer cell survival upon arginine deprivation.Cellular & molecular biology letters · 2025Article
- Arginine: at the crossroads of nitrogen metabolism.The EMBO journal · 2025Review
- Synergistic effects of L-arginine and argininosuccinate synthetase 1 in inducing apoptosis in hepatocellular carcinoma.Journal of liver cancer · 2025Article
- Proteomic analysis reveals potential biomarker candidates in serous ovarian tumors - a preliminary study.Contemporary oncology (Poznan, Poland) · 2025Article
- Computation suggests that the cell adhesion sub-proteome is enriched for sites of pH-dependence and charge burial.PloS one · 2025Article
- 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
- Discovery and Targeting of a Noncanonical Mechanism of Sarcoma Resistance to ADI-PEG20 Mediated by the Microenvironment.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Dietary Manipulation of Amino Acids for Cancer Therapy.Nutrients · 2023Review
- Bench-to-Bedside Studies of Arginine Deprivation in Cancer.Molecules (Basel, Switzerland) · 2023Review
- Melanoma stimulates the proteolytic activity of HaCaT keratinocytes.Cell communication and signaling : CCS · 2022Article
- PGAM1 regulation of ASS1 contributes to the progression of breast cancer through the cAMP/AMPK/CEBPB pathway.Molecular oncology · 2022Article
- 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
- Long noncoding RNA LINC01234 promotes hepatocellular carcinoma progression through orchestrating aspartate metabolic reprogramming.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
Corrections and comments
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Authors and funding
22 authors at 5 institutions in 2 countries.
Funding
Abstract
Downregulation of the urea cycle enzyme argininosuccinate synthase (ASS1) by either promoter methylation or by HIF1α is associated with increased metastasis and poor prognosis in multiple cancers. We have previously shown that in normoxic conditions, ASS1 downregulation facilitates cancer cell proliferation by increasing aspartate availability for pyrimidine synthesis by the enzyme complex CAD. Here we report that in hypoxia, ASS1 expression in cancerous cells is downregulated further by HIF1α-mediated induction of miR-224-5p, making the cells more invasive and dependent on upstream substrates of ASS1 for survival. ASS1 was downregulated under acidic conditions, and ASS1-depleted cancer cells maintained a higher intracellular pH (pHi), depended less on extracellular glutamine, and displayed higher glutathione levels. Depletion of substrates of urea cycle enzymes in ASS1-deficient cancers decreased cancer cell survival. Thus, ASS1 levels in cancer are differentially regulated in various environmental conditions to metabolically benefit cancer progression. Understanding these alterations may help uncover specific context-dependent cancer vulnerabilities that may be targeted for therapeutic purposes. SIGNIFICANCE: Cancer cells in an acidic or hypoxic environment downregulate the expression of the urea cycle enzyme ASS1, which provides them with a redox and pH advantage, resulting in better survival.
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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.