ArticleJournal of experimental & clinical cancer research : CR2021
Argininosuccinate synthase 1 suppresses tumor progression through activation of PERK/eIF2α/ATF4/CHOP axis in hepatocellular carcinoma.
Article in Journal of experimental & clinical cancer research : CR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 68 citations in OpenAlex.
- E7386 Enhances Lenvatinib's Antitumor Activity in Preclinical Models and Human Hepatocellular Carcinoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
- Trial
- GRP78/BiP as a novel midbody component induces mitotic exit failure via PLK1 stabilization in hepatocellular carcinoma.BMB reports · 2026Article
- Single-cell and machine learning reveal ROS-associated heterogeneity in hepatocellular carcinoma for precision medicine.BMC cancer · 2026Article
- The HKDC1-ASS1-ACSBG2 axis reprograms lipid metabolism to drive therapeutic resistance in hepatocellular carcinoma.Journal of translational medicine · 2026Article
- Impaired nitrogenous waste clearance promotes hepatocellular carcinoma.Science advances · 2026Article
- Targeting the unfolded protein response in cancer: mechanisms, small-molecule inhibitors, and translational challenges.Frontiers in immunology · 2026Review
- Endoplasmic reticulum stress-mediated cell death in spinal cord injury: from molecular mechanisms to therapeutic applications.Frontiers in cell and developmental biology · 2026Review
- Prediction of Biomarkers for Hepatocellular Carcinoma Based on Proteomics and Phosphoproteomics.International journal of general medicine · 2026Article
- SENP3 promotes renal tubular epithelial cell apoptosis after ischemia-reperfusion injury via ASS1 deSUMOylation.Cell death & disease · 2025Article
- AMPK-Dependent Epigenetic Regulation of Metabolism Mediates the Anti-Cancer Action of Pterostilbene in Hepatocellular Carcinoma.Molecular nutrition & food research · 2025Article
- Article
- mAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Etoposide-induced protein 2.4 homolog promotes argininosuccinate synthase 1 and cancer cell survival upon arginine deprivation.Cellular & molecular biology letters · 2025Article
- Synergistic effects of L-arginine and argininosuccinate synthetase 1 in inducing apoptosis in hepatocellular carcinoma.Journal of liver cancer · 2025Article
- Antitumor role of L-arginine and argininosuccinate synthetase 1 in hepatocellular carcinoma: direct and immunological mechanisms.Journal of liver cancer · 2025Article
- Arginine: at the crossroads of nitrogen metabolism.The EMBO journal · 2025Review
- Sestrin3 confers resistance to recombinant human arginase in small cell lung cancer by activating Akt/mTOR/ASS1 axis.PloS one · 2025Article
- EDEM1 Inhibits Endoplasmic Reticulum Stress to Induce Doxorubicin Resistance through Accelerating ERAD and Activating Keap1/Nrf2 Antioxidant Pathway in Triple-Negative Breast Cancer.Research (Washington, D.C.) · 2025Article
- The impact of metabolic reprogramming in hepatocellular carcinoma on T cell.Frontiers in immunology · 2025Review
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundHepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide, and liver cancer has increased in mortality due to liver cancer because it was detected at an advanced stages in patients with liver dysfunction, making HCC a lethal cancer. Accordingly, we aim to new targets for HCC drug discovery using HCC tumor spheroids.
methodsOur comparative proteomic analysis of HCC cells grown in culture as monolayers (2D) and spheroids (3D) revealed that argininosuccinate synthase 1 (ASS1) expression was higher in 3D cells than in 2D cells due to upregulated endoplasmic reticulum (ER) stress responses. We investigated the clinical value of ASS1 in Korean patients with HCC. The mechanism underlying ASS1-mediated tumor suppression was investigated in HCC spheroids. ASS1-mediated improvement of chemotherapy efficiency was observed using high content screening in an HCC xenograft mouse model.
resultsStudies of tumor tissue from Korean HCC patients showed that, although ASS1 expression was low in most samples, high levels of ASS1 were associated with favorable overall survival of patients. Here, we found that bidirectional interactions between ASS1 ER stress responses in HCC-derived multicellular tumor spheroids can limit HCC progression. ASS1 overexpression effectively inhibited tumor growth and enhanced the efficacy of in vitro and in vivo anti-HCC combination chemotherapy via activation of the PERK/eIF2α/ATF4/CHOP axis, but was not dependent on the status of p53 and arginine metabolism.
conclusionsThese results demonstrate the critical functional roles for the arginine metabolism-independent tumor suppressor activity of ASS1 in HCC and suggest that upregulating ASS1 in these tumors is a potential strategy in HCC cells with low ASS1 expression.
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