Journal
ONCOLOGY REPORTS
Volume 37, Issue 2, Pages 1036-1044Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/or.2016.5328
Keywords
regorafenib; ERK/NF-kappa B; hepatocellular carcinoma
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Funding
- National Yang-Ming University Hospital (Yilan, Taiwan) [RD2016-020]
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The aim of the present study was to investigate the role of NF-kappa B inactivation in regorafenib-induced apoptosis in human hepatocellular carcinoma SK-HEP-1 cells. SK-HEP-1 cells were treated with different concentrations of the NF-kappa B inhibitor 4-N-[2-(4-phenoxyphenyl)ethyl] quinazoline-4,6-diamine (QNZ) or regorafenib for different periods. The effects of QNZ and regorafenib on cell viability, expression of NF-kappa B-modulated anti-apoptotic proteins and apoptotic pathways were analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, western blotting, DNA gel electrophoresis, flow cytometry and NF-kappa B reporter gene assay. Inhibitors of various kinases including AKT, c-Jun N-terminal kinase (JNK), P38 and extracellular signal-regulated kinase (ERK) were used to evaluate the mechanism of regorafenib-induced NF-kappa B inactivation. The results demonstrated that both QNZ and regorafenib significantly inhibited the expression of antiapoptotic proteins and triggered extrinsic and intrinsic apoptosis. We also demonstrated that regorafenib inhibited NF-kappa B activation through ERK dephosphorylation. Taken all together, our findings indicate that regorafenib triggers extrinsic and intrinsic apoptosis through suppression of ERK/NF-kappa B activation in SK-HEP-1 cells.
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