RT Journal Article
T1 Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer
A1 González, Raúl
A1 Rodríguez-Hernández, María A.
A1 Negrete, María
A1 Ranguelova, Kalina
A1 Rossin, Aurelie
A1 Choya-Foces, Carmen
A1 de la Cruz-Ojeda, Patricia
A1 Miranda-Vizuete, Antonio
A1 Martínez-Ruiz, Antonio
A1 Rius-Pérez, Sergio
A1 Sastre, Juan
A1 Bárcena, José A.
A1 Hueber, Anne-Odile
A1 Padilla, C. Alicia
A1 Muntané, Jordi
K1 Apoptosis
K1 Cell proliferation
K1 CD95
K1 GSNOR
K1 Hepatocarcinoma
K1 Nrf2
K1 NOS3
K1 Thioredoxins
K1 Liver cancer
K1 Downregulation
K1 Proliferación celular
K1 S-Nitrosoglutatión
K1 Carcinoma hepatocelular
K1 Factor 2 relacionado con NF-E2
K1 Óxido nítrico sintasa de tipo III
K1 Tiorredoxinas
K1 Neoplasias hepáticas
K1 Regulación hacia abajo
AB 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.
PB Elsevier
YR 2020
FD 2020-07
LK http://hdl.handle.net/10668/4548
UL http://hdl.handle.net/10668/4548
LA en
NO González R, Rodríguez-Hernández MA, Negrete M, Ranguelova K, Rossin A, Choya-Foces C, et al. Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer. Redox Biol. 2020 Jul;34:101528
DS RISalud
RD Apr 19, 2025