Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer

Redox Biology

Anne-Odile Hueber¹  Antonio Martínez-Ruiz¹  María A. Rodríguez-Hernández²  Kalina Ranguelova²  Carmen Choya-Foces³  C. Alicia Padilla⁴  Jordi Muntané⁴  María Negrete⁵  Raúl González⁵  Aurelie Rossin⁵  Juan Sastre⁵  Sergio Rius-Pérez⁵  Antonio Miranda-Vizuete⁶  José A. Bárcena⁶  Patricia de la Cruz-Ojeda⁷ 

[1] Biomedical Research Network Center for Cardiovascular Diseases (CIBERCV), Madrid, Spain;Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd), Madrid, Spain;Bruker BioSpin Corporation, Billerica, MA, USA;Department of Physiology, Faculty of Pharmacy, University of Valencia. Burjassot, Valencia, Spain;Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen Del Rocío”/CSIC/University of Seville, Seville, Spain;Research Unit, Hospital University “Santa Cristina”, Health Research Institute “La Princesa” (IIS-IP), Madrid, Spain;Université Côte D'Azur, CNRS, Inserm, iBV, Nice, France;

关键词: Apoptosis;    Cell proliferation;    CD95;    GSNOR;    Hepatocarcinoma;    Nrf2;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown