Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer
Raúl González,
María A. Rodríguez-Hernández,
María Negrete,
Kalina Ranguelova,
Aurelie Rossin,
Carmen Choya-Foces,
Patricia de la Cruz-Ojeda,
Antonio Miranda-Vizuete,
Antonio Martínez-Ruiz,
Sergio Rius-Pérez,
Juan Sastre,
José A. Bárcena,
Anne-Odile Hueber,
C. Alicia Padilla,
Jordi Muntané
Affiliations
Raúl González
Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen Del Rocío”/CSIC/University of Seville, Seville, Spain; Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd), Madrid, Spain
María A. Rodríguez-Hernández
Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen Del Rocío”/CSIC/University of Seville, Seville, Spain; Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd), Madrid, Spain
María Negrete
Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen Del Rocío”/CSIC/University of Seville, Seville, Spain
Kalina Ranguelova
Bruker BioSpin Corporation, Billerica, MA, USA
Aurelie Rossin
Université Côte D'Azur, CNRS, Inserm, iBV, Nice, France
Carmen Choya-Foces
Research Unit, Hospital University “Santa Cristina”, Health Research Institute “La Princesa” (IIS-IP), Madrid, Spain; Biomedical Research Network Center for Cardiovascular Diseases (CIBERCV), Madrid, Spain
Patricia de la Cruz-Ojeda
Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen Del Rocío”/CSIC/University of Seville, Seville, Spain
Antonio Miranda-Vizuete
Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen Del Rocío”/CSIC/University of Seville, Seville, Spain
Antonio Martínez-Ruiz
Research Unit, Hospital University “Santa Cristina”, Health Research Institute “La Princesa” (IIS-IP), Madrid, Spain; Biomedical Research Network Center for Cardiovascular Diseases (CIBERCV), Madrid, Spain
Sergio Rius-Pérez
Department of Physiology, Faculty of Pharmacy, University of Valencia. Burjassot, Valencia, Spain
Juan Sastre
Department of Physiology, Faculty of Pharmacy, University of Valencia. Burjassot, Valencia, Spain
José A. Bárcena
Department of Biochemistry and Molecular Biology, University of Cordoba, Cordoba, Spain; Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain
Anne-Odile Hueber
Université Côte D'Azur, CNRS, Inserm, iBV, Nice, France
C. Alicia Padilla
Department of Biochemistry and Molecular Biology, University of Cordoba, Cordoba, Spain; Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain
Jordi Muntané
Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen Del Rocío”/CSIC/University of Seville, Seville, Spain; Department of General Surgery, Hospital University ''Virgen del Rocío''/IBiS/CSIC/University of Seville, Seville, Spain; Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd), Madrid, Spain; Corresponding author. Instituto de Biomedicina de Sevilla (IBiS), Av. Manuel Siurot s/n, 41013, Sevilla, Spain.
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.
