https://scholars.lib.ntu.edu.tw/handle/123456789/383123
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.author | Kuen-Feng Chen | en |
dc.creator | Tai, W.-T. and Shiau, C.-W. and Li, Y.-S. and Chang, C.-W. and Huang, J.-W. and Hsueh, T.-T. and Yu, H.-C. and Chen, K.-F. | - |
dc.date.accessioned | 2018-09-10T14:50:05Z | - |
dc.date.available | 2018-09-10T14:50:05Z | - |
dc.date.issued | 2014 | - |
dc.identifier.uri | http://www.scopus.com/inward/record.url?eid=2-s2.0-84902662529&partnerID=MN8TOARS | - |
dc.identifier.uri | http://scholars.lib.ntu.edu.tw/handle/123456789/383123 | - |
dc.description.abstract | Background & Aims Nintedanib, a triple angiokinase inhibitor, is currently being evaluated against advanced HCC in phase I/II clinical trials. Here, we report the underlying molecular mechanism by which nintedanib (BIBF-1120) induces an anti-HCC effect. Methods To further elucidate whether the effect of nintedanib on SHP-1 is dependent on its angiokinase inhibition activity, we developed a novel kinase-independent derivative of nintedanib, ΔN. HCC cell lines were treated with nintedanib or its derivative (ΔN) and apoptosis, signal transduction, and phosphatase activity were analyzed. Purified SHP-1 proteins or HCC cells expressing deletion N-SH2 domain or D61A point mutants were used to investigate the potential effect of nintedanib on SHP-1. In vivo efficacy was determined in nude mice with HCC subcutaneous xenografts (n ? 8 mice). Results Nintedanib induced anti-proliferation in HCC cell lines by targeting STAT3. Ectopic STAT3 abolished nintedanib-mediated apoptosis in HCC cells. Nintedanib further activated SHP-1 in purified SHP-1 proteins suggesting that nintedanib directly affects SHP-1 for STAT3 inhibition. HCC cells or recombinant SHP-1 proteins expressing deletion of N-SH2 domain or D61A mutants restored the activity of nintedanib suggesting that the auto-inhibition structure of SHP-1 was relieved by nintedanib. Although ΔN only retained the backbone of nintedanib without kinase activity, ΔN still induced substantial anti-HCC activity in vitro and in vivo by targeting STAT3. Conclusions Nintedanib induced significant anti-HCC activity independent of angiokinase inhibition activity in a preclinical HCC model by relieving autoinhibition of SHP-1. Our findings provide new mechanistic insight into the inhibition of HCC growth by nintedanib. ? 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. | - |
dc.language | en | en |
dc.relation.ispartof | Journal of Hepatology | en_US |
dc.source | AH | - |
dc.subject.classification | [SDGs]SDG3 | - |
dc.subject.other | actin; caspase 9; cyclin D1; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; nintedanib; phosphatase; protein tyrosine phosphatase SHP 1; STAT3 protein; survivin; tissue plasminogen activator; antineoplastic agent; indole derivative; mutant protein; nintedanib; protein kinase inhibitor; protein tyrosine kinase; protein tyrosine phosphatase SHP 1; PTPN6 protein, human; STAT3 protein; STAT3 protein, human; animal experiment; antiproliferative activity; apoptosis; article; cancer inhibition; controlled study; enzyme activity; enzyme linked immunosorbent assay; hepatoblastoma cell line; human; human cell; in vitro study; liver cell carcinoma; male; mouse; nonhuman; point mutation; priority journal; protein expression; protein phosphorylation; signal transduction; tumor xenograft; animal; antagonists and inhibitors; binding site; Carcinoma, Hepatocellular; cell proliferation; chemical structure; chemistry; drug effects; drug screening; enzymology; genetics; Liver Neoplasms; metabolism; nude mouse; pathology; protein conformation; tumor cell line; Animals; Antineoplastic Agents; Apoptosis; Binding Sites; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Humans; Indoles; Liver Neoplasms; Male; Mice; Mice, Nude; Models, Molecular; Mutant Proteins; Protein Conformation; Protein Kinase Inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Receptor Protein-Tyrosine Kinases; Signal Transduction; STAT3 Transcription Factor; Xenograft Model Antitumor Assays | - |
dc.title | Nintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity | - |
dc.type | journal article | en |
dc.identifier.doi | 10.1016/j.jhep.2014.03.017 | - |
dc.relation.pages | 89-97 | - |
dc.relation.journalvolume | 61 | - |
dc.relation.journalissue | 1 | - |
item.openairecristype | http://purl.org/coar/resource_type/c_6501 | - |
item.openairetype | journal article | - |
item.grantfulltext | none | - |
item.cerifentitytype | Publications | - |
item.fulltext | no fulltext | - |
crisitem.author.dept | Medical Research | - |
crisitem.author.orcid | 0000-0002-4686-7019 | - |
crisitem.author.parentorg | National Taiwan University Hospital | - |
顯示於: | 醫學系 |
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