Redox Biol. 2020 Jul;34:101528. doi: 10.1016/j.redox.2020.101528. Epub 2020 Apr 4.

Raúl González  ¹ , María A Rodríguez-Hernández  ¹ , María Negrete  ² , Kalina Ranguelova  ³ , Aurelie Rossin  ⁴ , Carmen Choya-Foces  ⁵ , Patricia de la Cruz-Ojeda  ² , Antonio Miranda-Vizuete  ² , Antonio Martínez-Ruiz  ⁵ , Sergio Rius-Pérez  ⁶ , Juan Sastre  ⁶ , José A Bárcena  ⁷ , Anne-Odile Hueber  ⁴ , C Alicia Padilla  ⁷ , Jordi Muntané  ⁸

Affiliations

¹ 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.
² Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen Del Rocío”/CSIC/University of Seville, Seville, Spain.
³ Bruker BioSpin Corporation, Billerica, MA, USA.
⁴ Université Côte D’Azur, CNRS, Inserm, iBV, Nice, France.
⁵ 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.
⁶ Department of Physiology, Faculty of Pharmacy, University of Valencia. Burjassot, Valencia, Spain.
⁷ Department of Biochemistry and Molecular Biology, University of Cordoba, Cordoba, Spain; Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain.
⁸ 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. Electronic address: jmuntane-ibis@us.es.

Abstract

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.

PMID: 32388267
DOI: 10.1016/j.redox.2020.101528