Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer
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 prese...
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Elsevier
2020-07-01
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231720304882 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer Redox Biology Apoptosis Cell proliferation CD95 GSNOR Hepatocarcinoma Nrf2 |
author_facet |
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 |
author_sort |
Raúl González |
title |
Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer |
title_short |
Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer |
title_full |
Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer |
title_fullStr |
Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer |
title_full_unstemmed |
Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer |
title_sort |
downregulation of thioredoxin-1-dependent cd95 s-nitrosation by sorafenib reduces liver cancer |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2020-07-01 |
description |
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. |
topic |
Apoptosis Cell proliferation CD95 GSNOR Hepatocarcinoma Nrf2 |
url |
http://www.sciencedirect.com/science/article/pii/S2213231720304882 |
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doaj-a773d763af1a4f16b908e005722e555a2020-11-25T03:22:59ZengElsevierRedox Biology2213-23172020-07-0134101528Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancerRaúl González0María A. Rodríguez-Hernández1María Negrete2Kalina Ranguelova3Aurelie Rossin4Carmen Choya-Foces5Patricia de la Cruz-Ojeda6Antonio Miranda-Vizuete7Antonio Martínez-Ruiz8Sergio Rius-Pérez9Juan Sastre10José A. Bárcena11Anne-Odile Hueber12C. Alicia Padilla13Jordi Muntané14Institute 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, SpainInstitute 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, SpainInstitute of Biomedicine of Seville (IBiS), Hospital University “Virgen Del Rocío”/CSIC/University of Seville, Seville, SpainBruker BioSpin Corporation, Billerica, MA, USAUniversité Côte D'Azur, CNRS, Inserm, iBV, Nice, FranceResearch Unit, Hospital University “Santa Cristina”, Health Research Institute “La Princesa” (IIS-IP), Madrid, Spain; Biomedical Research Network Center for Cardiovascular Diseases (CIBERCV), Madrid, SpainInstitute of Biomedicine of Seville (IBiS), Hospital University “Virgen Del Rocío”/CSIC/University of Seville, Seville, SpainInstitute of Biomedicine of Seville (IBiS), Hospital University “Virgen Del Rocío”/CSIC/University of Seville, Seville, SpainResearch Unit, Hospital University “Santa Cristina”, Health Research Institute “La Princesa” (IIS-IP), Madrid, Spain; Biomedical Research Network Center for Cardiovascular Diseases (CIBERCV), Madrid, SpainDepartment of Physiology, Faculty of Pharmacy, University of Valencia. Burjassot, Valencia, SpainDepartment of Physiology, Faculty of Pharmacy, University of Valencia. Burjassot, Valencia, SpainDepartment of Biochemistry and Molecular Biology, University of Cordoba, Cordoba, Spain; Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, SpainUniversité Côte D'Azur, CNRS, Inserm, iBV, Nice, FranceDepartment of Biochemistry and Molecular Biology, University of Cordoba, Cordoba, Spain; Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, SpainInstitute 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.http://www.sciencedirect.com/science/article/pii/S2213231720304882ApoptosisCell proliferationCD95GSNORHepatocarcinomaNrf2 |