title: Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells.
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 (10 µM) 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.
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital Universitario "Virgen del Rocío"/CSIC/Universidad de Sevilla, Av. Manuel Siurot s/n, 41013 Sevilla, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez-Hernández
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital Universitario "Virgen del Rocío"/CSIC/Universidad de Sevilla, Av. Manuel Siurot s/n, 41013 Sevilla, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Navarro-Villarán
authors.affiliation: Departament of Biochemistry and Molecular Biology, University of Cordoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14071 Córdoba, Spain.
authors.forename: R
authors.initials: R
authors.lastname: González
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital Universitario "Virgen del Rocío"/CSIC/Universidad de Sevilla, Av. Manuel Siurot s/n, 41013 Sevilla, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Pereira
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital Universitario "Virgen del Rocío"/CSIC/Universidad de Sevilla, Av. Manuel Siurot s/n, 41013 Sevilla, Spain.
authors.forename: L B
authors.initials: LB
authors.lastname: Soriano-De Castro
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital Universitario "Virgen del Rocío"/CSIC/Universidad de Sevilla, Av. Manuel Siurot s/n, 41013 Sevilla, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Sarrias-Giménez
authors.affiliation: Department of General Surgery, Hospital Universitario "Virgen del Rocío" - "Virgen Macarena"/Instituto de Biomedicina de Sevilla (IBiS)/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Barrera-Pulido
authors.affiliation: Department of General Surgery, Hospital Universitario "Virgen del Rocío" - "Virgen Macarena"/Instituto de Biomedicina de Sevilla (IBiS)/CSIC/Universidad de Sevilla, Sevilla, Spain; CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Álamo-Martínez
authors.affiliation: Hepato-Biliary Surgery Unit, Hospital Universitario "Miguel Servet", Zaragoza, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Serrablo-Requejo
authors.affiliation: Hepato-Biliary-Pancreatic and Liver Transplant Service, Hospital Universitario "Infanta Cristina", Badajoz, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Blanco-Fernández
authors.affiliation: Department of General Surgery, Hospital Universitario "Virgen del Rocío" - "Virgen Macarena"/Instituto de Biomedicina de Sevilla (IBiS)/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Nogales-Muñoz
authors.affiliation: Department of General Surgery, Hospital Universitario "Virgen del Rocío" - "Virgen Macarena"/Instituto de Biomedicina de Sevilla (IBiS)/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gila-Bohórquez
authors.affiliation: Department of General Surgery and Department of Pathology, Hospital Universitario "Rio Hortega", Valladolid, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Pacheco
authors.affiliation: Department of Pathology, Hospital Universitario "Rio Hortega", Valladolid, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Torres-Nieto
authors.affiliation: Department of General Surgery, Hospital Universitario "Virgen del Rocío" - "Virgen Macarena"/Instituto de Biomedicina de Sevilla (IBiS)/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Serrano-Díaz-Canedo
authors.affiliation: Department of General Surgery, Hospital Universitario "Virgen del Rocío" - "Virgen Macarena"/Instituto de Biomedicina de Sevilla (IBiS)/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Suárez-Artacho
authors.affiliation: Department of General Surgery, Hospital Universitario "Virgen del Rocío" - "Virgen Macarena"/Instituto de Biomedicina de Sevilla (IBiS)/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Bernal-Bellido
authors.affiliation: Department of General Surgery, Hospital Universitario "Virgen del Rocío" - "Virgen Macarena"/Instituto de Biomedicina de Sevilla (IBiS)/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: L M
authors.initials: LM
authors.lastname: Marín-Gómez
authors.affiliation: Departament of Biochemistry and Molecular Biology, University of Cordoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14071 Córdoba, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Barcena
authors.affiliation: Department of General Surgery, Hospital Universitario "Virgen del Rocío" - "Virgen Macarena"/Instituto de Biomedicina de Sevilla (IBiS)/CSIC/Universidad de Sevilla, Sevilla, Spain; CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Gómez-Bravo
authors.affiliation: Departament of Biochemistry and Molecular Biology, University of Cordoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14071 Córdoba, Spain.
authors.forename: C A
authors.initials: CA
authors.lastname: Padilla
authors.affiliation: Department of General Surgery, Hospital Universitario "Virgen del Rocío" - "Virgen Macarena"/Instituto de Biomedicina de Sevilla (IBiS)/CSIC/Universidad de Sevilla, Sevilla, Spain; CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain.
authors.forename: F J
authors.initials: FJ
authors.lastname: Padillo
authors.affiliation: Department of General Surgery, Hospital Universitario "Virgen del Rocío" - "Virgen Macarena"/Instituto de Biomedicina de Sevilla (IBiS)/CSIC/Universidad de Sevilla, Sevilla, Spain; CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain. Electronic address: jmuntane-ibis@us.es.
authors.forename: J
authors.initials: J
authors.lastname: Muntané
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009569:Nitric Oxide / Q000737:chemistry / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D026403:S-Nitrosothiols / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D020030:Nitric Oxide Donors; D010671:Phenylurea Compounds; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D047888:Receptors, Tumor Necrosis Factor, Type I; D026403:S-Nitrosothiols; D009536:Niacinamide; D009569:Nitric Oxide; C021315:S-nitrosocysteine; D000077157:Sorafenib; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D003545:Cysteine
keywords: Apoptosis; Death-receptors; Hepatoblastoma; NO; S-nitrosylation; Sorafenib