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Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells.
- Source :
-
Redox biology [Redox Biol] 2015 Dec; Vol. 6, pp. 174-182. Date of Electronic Publication: 2015 Jul 22. - Publication Year :
- 2015
-
Abstract
- Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.<br /> (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Caspase 3 genetics
Caspase 3 metabolism
Caspase 8 genetics
Caspase 8 metabolism
Caspase 9 genetics
Caspase 9 metabolism
Cell Death drug effects
Cysteine analogs & derivatives
Cysteine chemistry
Cysteine pharmacology
Hep G2 Cells
Humans
Niacinamide pharmacology
Nitric Oxide chemistry
Nitric Oxide pharmacology
Nitric Oxide Donors chemistry
Nitric Oxide Donors pharmacology
Nitric Oxide Synthase Type III genetics
Nitric Oxide Synthase Type III metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand genetics
Receptors, Tumor Necrosis Factor, Type I genetics
S-Nitrosothiols chemistry
S-Nitrosothiols pharmacology
Sorafenib
Antineoplastic Agents pharmacology
Gene Expression Regulation, Neoplastic
Niacinamide analogs & derivatives
Phenylurea Compounds pharmacology
Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism
Receptors, Tumor Necrosis Factor, Type I metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 2213-2317
- Volume :
- 6
- Database :
- MEDLINE
- Journal :
- Redox biology
- Publication Type :
- Academic Journal
- Accession number :
- 26233703
- Full Text :
- https://doi.org/10.1016/j.redox.2015.07.010