https://scholars.lib.ntu.edu.tw/handle/123456789/383123
Title: | Nintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity | Authors: | Kuen-Feng Chen | Issue Date: | 2014 | Journal Volume: | 61 | Journal Issue: | 1 | Start page/Pages: | 89-97 | Source: | Journal of Hepatology | 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. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-84902662529&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/383123 |
DOI: | 10.1016/j.jhep.2014.03.017 | SDG/Keyword: | 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 |
Appears in Collections: | 醫學系 |
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