6533b858fe1ef96bd12b59f3
RESEARCH PRODUCT
Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer
Sergio Rius-pérezCarmen Choya-focesJordi MuntanéMaría A. Rodríguez-hernándezAntonio Miranda-vizueteC. Alicia PadillaRaúl GonzálezAntonio Martínez-ruizJuan SastreMaría NegretePatricia De La Cruz-ojedaKalina RanguelovaAnne-odile HueberJosé Antonio BárcenaAurélie Rossinsubject
0301 basic medicine:Anatomy::Cells::Cells Cultured::Cell Line::Cell Line Tumor [Medical Subject Headings]Factor 2 relacionado con NF-E2Regulación hacia abajomedicine.medical_treatment[SDV]Life Sciences [q-bio]Clinical Biochemistry:Chemicals and Drugs::Amino Acids Peptides and Proteins::Proteins::Thioredoxins [Medical Subject Headings]ApoptosisBiochemistry:Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Nitrosation [Medical Subject Headings]Targeted therapyNeoplasias hepáticas:Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings]Mice0302 clinical medicineThioredoxins:Organisms::Eukaryota::Animals [Medical Subject Headings]lcsh:QH301-705.5Cell proliferationlcsh:R5-920GSNORChemistry:Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Liver Neoplasms [Medical Subject Headings]Liver NeoplasmsSorafenibFas receptor3. Good healthHepatocellular carcinomaCD95Liver cancerlcsh:Medicine (General)NOS3Liver cancerCarcinoma hepatocelularResearch Papermedicine.drugSorafenibHepatocarcinomaProliferación celularCarcinoma HepatocellularNitrosationDown-RegulationMice Nude[SDV.CAN]Life Sciences [q-bio]/CancerAntineoplastic AgentsNrf203 medical and health sciencesDownregulation and upregulationCell Line TumormedicineAnimalsHumansS-NitrosoglutatiónTiorredoxinas:Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell Proliferation [Medical Subject Headings]:Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings]:Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Liver Neoplasms::Carcinoma Hepatocellular [Medical Subject Headings]:Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Down-Regulation [Medical Subject Headings]Cell growthPhenylurea CompoundsOrganic Chemistry:Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [Medical Subject Headings][SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology:Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice Mutant Strains::Mice Nude [Medical Subject Headings]medicine.diseasedigestive system diseases030104 developmental biologylcsh:Biology (General)ApoptosisDownregulation:Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Hydrocarbons Cyclic::Hydrocarbons Aromatic::Benzene Derivatives::Phenylurea Compounds [Medical Subject Headings][SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/PharmacologyCancer researchÓxido nítrico sintasa de tipo III030217 neurology & neurosurgerydescription
Hepatocellular 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-07-01 |