González, RaúlRodríguez-Hernández, María A.Negrete, MaríaRanguelova, KalinaRossin, AurelieChoya-Foces, Carmende la Cruz-Ojeda, PatriciaMiranda-Vizuete, AntonioMartínez-Ruiz, AntonioRius-Pérez, SergioSastre, JuanBárcena, José A.Hueber, Anne-OdilePadilla, C. AliciaMuntané, Jordi2023-01-092023-01-092020-07González R, Rodríguez-Hernández MA, Negrete M, Ranguelova K, Rossin A, Choya-Foces C, et al. Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer. Redox Biol. 2020 Jul;34:101528http://hdl.handle.net/10668/4548Hepatocellular carcinoma (HCC) represents 80% of the primary hepatic neoplasms. It is the sixth most frequent neoplasm, the fourth cause of cancer-related death, and 7% of registered malignancies. Sorafenib is the first line molecular targeted therapy for patients in advanced stage of HCC. The present study shows that Sorafenib exerts free radical scavenging properties associated with the downregulation of nuclear factor E2-related factor 2 (Nrf2)-regulated thioredoxin 1 (Trx1) expression in liver cancer cells. The experimental downregulation and/or overexpression strategies showed that Trx1 induced activation of nitric oxide synthase (NOS) type 3 (NOS3) and S-nitrosation (SNO) of CD95 receptor leading to an increase of caspase-8 activity and cell proliferation, as well as reduction of caspase-3 activity in liver cancer cells. In addition, Sorafenib transiently increased mRNA expression and activity of S-nitrosoglutathione reductase (GSNOR) in HepG2 cells. Different experimental models of hepatocarcinogenesis based on the subcutaneous implantation of HepG2 cells in nude mice, as well as the induction of HCC by diethylnitrosamine (DEN) confirmed the relevance of Trx1 downregulation during the proapoptotic and antiproliferative properties induced by Sorafenib. In conclusion, the induction of apoptosis and antiproliferative properties by Sorafenib were related to Trx1 downregulation that appeared to play a relevant role on SNO of NOS3 and CD95 in HepG2 cells. The transient increase of GSNOR might also participate in the deactivation of CD95-dependent proliferative signaling in liver cancer cells.enAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/ApoptosisCell proliferationCD95GSNORHepatocarcinomaNrf2NOS3ThioredoxinsLiver cancerDownregulationProliferación celularS-NitrosoglutatiónCarcinoma hepatocelularFactor 2 relacionado con NF-E2Óxido nítrico sintasa de tipo IIITiorredoxinasNeoplasias hepáticasRegulación hacia abajoMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, TumorMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell ProliferationMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Down-RegulationMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, NudeMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::NitrosationMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Hydrocarbons, Cyclic::Hydrocarbons, Aromatic::Benzene Derivatives::Phenylurea CompoundsMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::ThioredoxinsMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic AgentsMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Liver Neoplasms::Carcinoma, HepatocellularMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Liver Neoplasmsresearch article32388267open access10.1016/j.redox.2020.1015282213-2317PMC7210585