Rodríguez-Hernández, A.Navarro-Villarán, E.González, R.Pereira, S.Soriano-De Castro, L. B.Sarrias-Giménez, A.Barrera-Pulido, L.Álamo-Martínez, J. M.Serrablo-Requejo, A.Blanco-Fernández, G.Nogales-Muñoz, A.Gila-Bohórquez, A.Pacheco, D.Torres-Nieto, M. A.Serrano-Díaz-Canedo, J.Suárez-Artacho, G.Bernal-Bellido, C.Marín-Gómez, L. M.Barcena, J. A.Gómez-Bravo, M. A.Padilla, C. A.Padillo, F. J.Muntané, J.2015-10-052015-10-052015-07-22Rodríguez-Hernández A, Navarro-Villarán E, González R, Pereira S, Soriano-De Castro LB, Sarrias-Giménez A, et al. Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells. Redox Biol. 2015 ; 6:174-182http://hdl.handle.net/10668/2005JOURNAL ARTICLE;Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.spaApoptosisDeath-receptorsHepatoblastomaNOS-nitrosylationSorafenibCaspasa 3Caspasa 8Muerte CelularNeoplasias HepáticasÓxido NítricoCompuestos de FenilureaMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::ApoptosisMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Glandular and Epithelial::Carcinoma::Adenocarcinoma::Carcinoma, HepatocellularMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Peptide Hydrolases::Cysteine Proteases::Cysteine Endopeptidases::Caspases::Caspases, Effector::Caspase 3Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Peptide Hydrolases::Cysteine Proteases::Cysteine Endopeptidases::Caspases::Caspases, Initiator::Caspase 8Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell DeathMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA Damage::DNA FragmentationMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Tumor Cells, Cultured::Cell Line, Tumor::Hep G2 CellsMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Complex and Mixed::HepatoblastomaMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Diseases::Digestive System Diseases::Digestive System Neoplasms::Liver NeoplasmsMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Acids, Heterocyclic::Nicotinic Acids::NiacinamideMedical Subject Headings::Chemicals and Drugs::Inorganic Chemicals::Free Radicals::Nitric OxideMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Nitric Oxide DonorsMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Oxidoreductases Acting on CH-NH2 Group Donors::Amino Acid Oxidoreductases::Nitric Oxide Synthase::Nitric Oxide Synthase Type IIIMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Urea::Phenylurea CompoundsMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Death Domainresearch article26233703open access10.1016/j.redox.2015.07.0102213-2317