Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells

Tsai,Jai-Jen; Pan,Po-Jung; Hsu,Fei-Ting

doi:10.3892/or.2016.5328

Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells

Authors:
- Jai-Jen Tsai
- Po-Jung Pan
- Fei-Ting Hsu
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Affiliations: Division of Gastroenterology, Department of Medicine, National Yang-Ming University Hospital, Yilan 260, Taiwan, R.O.C., Cancer Medical Care Center, National Yang‑Ming University Hospital, Yilan 260, Taiwan, R.O.C., Department of Medical Imaging, Taipei Medical University Hospital, Taipei 110, Taiwan, R.O.C.
Published online on: December 20, 2016 https://doi.org/10.3892/or.2016.5328
Pages: 1036-1044

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Abstract

The aim of the present study was to investigate the role of NF-κB 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-κB 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-κB-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-κB 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-κB inactivation. The results demonstrated that both QNZ and regorafenib significantly inhibited the expression of anti-apoptotic proteins and triggered extrinsic and intrinsic apoptosis. We also demonstrated that regorafenib inhibited NF-κB activation through ERK dephosphorylation. Taken all together, our findings indicate that regorafenib triggers extrinsic and intrinsic apoptosis through suppression of ERK/NF-κB activation in SK-HEP-1 cells.

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