Publication:
Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells.

Research Projects
Organizational Units
Journal Issue
Abstract
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.
Description
JOURNAL ARTICLE;
MeSH Terms
Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Apoptosis
Medical Subject Headings::Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Glandular and Epithelial::Carcinoma::Adenocarcinoma::Carcinoma, Hepatocellular
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Peptide Hydrolases::Cysteine Proteases::Cysteine Endopeptidases::Caspases::Caspases, Effector::Caspase 3
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Peptide Hydrolases::Cysteine Proteases::Cysteine Endopeptidases::Caspases::Caspases, Initiator::Caspase 8
Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA Damage::DNA Fragmentation
Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Tumor Cells, Cultured::Cell Line, Tumor::Hep G2 Cells
Medical Subject Headings::Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Complex and Mixed::Hepatoblastoma
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Diseases::Digestive System Diseases::Digestive System Neoplasms::Liver Neoplasms
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Acids, Heterocyclic::Nicotinic Acids::Niacinamide
Medical Subject Headings::Chemicals and Drugs::Inorganic Chemicals::Free Radicals::Nitric Oxide
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Nitric Oxide Donors
Medical 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 III
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Urea::Phenylurea Compounds
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Death Domain
DeCS Terms
CIE Terms
Keywords
Apoptosis, Death-receptors, Hepatoblastoma, NO, S-nitrosylation, Sorafenib, Caspasa 3, Caspasa 8, Muerte Celular, Neoplasias Hepáticas, Óxido Nítrico, Compuestos de Fenilurea
Citation
Rodríguez-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 ; 6:174-182