title: Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells.
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.
authors.affiliation: Division of Gastroenterology, Department of Medicine, National Yang-Ming University Hospital, Yilan 260, Taiwan, R.O.C.
authors.forename: Jai-Jen
authors.initials: JJ
authors.lastname: Tsai
authors.affiliation: Cancer Medical Care Center, National Yang‑Ming University Hospital, Yilan 260, Taiwan, R.O.C.
authors.forename: Po-Jung
authors.initials: PJ
authors.lastname: Pan
authors.affiliation: Department of Medical Imaging, Taipei Medical University Hospital, Taipei 110, Taiwan, R.O.C.
authors.forename: Fei-Ting
authors.initials: FT
authors.lastname: Hsu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010647:Phenyl Ethers / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C562064:EVP 4593; D016328:NF-kappa B; D010647:Phenyl Ethers; D010671:Phenylurea Compounds; D011725:Pyridines; D011799:Quinazolines; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C559147:regorafenib; D048049:Extracellular Signal-Regulated MAP Kinases