https://scholars.lib.ntu.edu.tw/handle/123456789/565036
標題: | Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma | 作者: | Tai W.-T. ANN-LII CHENG Shiau C.-W. HSIANG-PO HUANG Huang J.-W. PEI-JER CHEN Chen K.-F. |
公開日期: | 2011 | 出版社: | Elsevier B.V. | 卷: | 55 | 期: | 5 | 起(迄)頁: | 1041-1048 | 來源出版物: | Journal of Hepatology | 摘要: | Background & Aims: Recently, we reported that sorafenib sensitizes hepatocellular carcinoma (HCC) cells to TRAIL through the inhibition of signal transducer and activator of transcription 3 (STAT3). Here, we report that sorafenib inhibits HCC via a kinase-independent mechanism: SHP-1 dependent STAT3 inactivation. Methods: SC-1 is a sorafenib derivative that closely resembles sorafenib structurally but with no kinase inhibition activity. HCC cell lines (PLC5, Huh-7, Hep3B, and Sk-Hep1) were treated with sorafenib or SC-1 and apoptosis and signal transduction were analyzed. In vivo efficacy was determined in nude mice with Huh-7 xenografts. Results: SC-1 showed similar effects to sorafenib on growth inhibition and apoptosis in all tested HCC cell lines. SC-1 down-regulated phosphorylation of phospho-STAT3 (p-STAT3) at tyrosine 705 in all tested HCC cells. Expression of STAT3-driven genes, including Cyclin D1 and Survivin, was also repressed by SC-1. Luciferase reporter assay confirmed the inhibition of transcriptional activity of STAT3 in both sorafenib-treated and SC-1-treated cells. Ectopic expression of STAT3 in PLC5 cells abolished apoptosis in SC-1-treated cells. Sorafenib and SC-1 up-regulated SHP-1 activity. Knockdown of SHP-1, but not SHP-2 or PTP-1B, by small interference RNA reduced apoptosis induced by SC-1. Finally, SC-1 reduced Huh-7 tumor growth significantly in vivo, which was associated with down-regulation of p-STAT3 and up-regulation of SHP-1 activity. Conclusions: STAT3 is a major kinase-independent target of sorafenib in HCC. ? 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84984589185&doi=10.1016%2fj.jhep.2011.01.047&partnerID=40&md5=1bd737f0bf1832773ff5a06c865272f4 https://scholars.lib.ntu.edu.tw/handle/123456789/565036 |
ISSN: | 0168-8278 | DOI: | 10.1016/j.jhep.2011.01.047 | SDG/關鍵字: | antineoplastic agent; cyclin D1; drug metabolite; protein tyrosine phosphatase SHP 1; sc 1; small interfering RNA; sorafenib; STAT3 protein; survivin; unclassified drug; animal experiment; animal model; antineoplastic activity; apoptosis; article; cancer inhibition; controlled study; down regulation; drug dose escalation; drug efficacy; drug targeting; enzyme activity; human; human cell; in vivo study; liver cell carcinoma; male; mouse; nonhuman; priority journal; protein expression; protein phosphorylation; signal transduction; structure activity relation; tumor xenograft |
顯示於: | 基因體暨蛋白體醫學研究所 |
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