Article
Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cáncer
Author/s | González, Raúl
Rodríguez-Hernández, María A. Negrete, María Ranguelova, Kalina Rossin, Aurelie Choya-Foces, Carmen Cruz-Ojeda, Patricia de la Muntané Relat, Jordi |
Department | Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica |
Publication Date | 2020 |
Deposit Date | 2023-05-19 |
Published in |
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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 ... 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. |
Funding agencies | Andalusian Ministry of Economy, Innovation, Science and Employment Andalusian Ministry of Equality, Health and Social Policies European Development Regional Fund "A way to achieve Europe" ERDF FPU predoctoral fellowship from Ministry of Education, Culture and Sports Institute of Health Carlos III (ISCIII) Spanish Ministry of Economy and Competitiveness |
Project ID. | BIO-216; CTS-6264
PI-00025-2013; PI-0198-2016 FPU17/00026 PI13/00021; PI15/00107; PI16/00090; PI19/01266 SAF2015-71208-R; BFU2016-8006-P; PGC2018-094276-B-I00; RED2018-102576-T |
Citation | González, R., Rodríguez-Hernández, M.A., Negrete, M., Ranguelova, K., Rossin, A., Choya-Foces, C.,...,Muntané Relat, J. (2020). Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cáncer. Redox Biology, 34, UNSP 101528. https://doi.org/10.1016/j.redox.2020.101528. |
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