https://scholars.lib.ntu.edu.tw/handle/123456789/580223
標題: | Mcl-1-dependent activation of Beclin 1 mediates autophagic cell death induced by sorafenib and SC-59 in hepatocellular carcinoma cells | 作者: | Tai W.-T. Shiau C.-W. Chen H.-L. Liu C.-Y. Lin C.-S. ANN-LII CHENG PEI-JER CHEN Chen K.-F. |
公開日期: | 2013 | 出版社: | Nature Publishing Group | 卷: | 4 | 期: | 2 | 來源出版物: | Cell Death and Disease | 摘要: | We investigated the molecular mechanisms underlying the effect of sorafenib and SC-59, a novel sorafenib derivative, on hepatocellular carcinoma (HCC). Sorafenib activated autophagy in a dose- and time-dependent manner in the HCC cell lines PLC5, Sk-Hep1, HepG2 and Hep3B. Sorafenib downregulated phospho-STAT3 (P-STAT3) and subsequently reduced the expression of myeloid cell leukemia-1 (Mcl-1). Inhibition of Mcl-1 by sorafenib resulted in disruption of the Beclin 1-Mcl-1 complex; however, sorafenib did not affect the amount of Beclin 1, suggesting that sorafenib treatment released Beclin 1 from binding with Mcl-1. Silencing of SHP-1 by small interference RNA (siRNA) reduced the effect of sorafenib on P-STAT3 and autophagy. Ectopic expression of Mcl-1 abolished the effect of sorafenib on autophagy. Knockdown of Beclin 1 by siRNA protected the cells from sorafenib-induced autophagy. Moreover, SC-59, a sorafenib derivative, had a more potent effect on cancer cell viability than sorafenib. SC-59 downregulated P-STAT3 and induced autophagy in all tested HCC cell lines. Furthermore, our in vivo data showed that both sorafenib and SC-59 inhibited tumor growth, downregulated P-STAT3, enhanced the activity of SHP-1 and induced autophagy in PLC5 tumors, suggesting that sorafenib and SC-59 activate autophagy in HCC. In conclusion, sorafenib and SC-59 induce autophagy in HCC through a SHP-1-STAT3-Mcl-1-Beclin 1 pathway. ? 2013 Macmillan Publishers Limited All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84983718691&doi=10.1038%2fcddis.2013.18&partnerID=40&md5=6c5dd35dde1960a1dba9fb47127a4b3b https://scholars.lib.ntu.edu.tw/handle/123456789/580223 |
DOI: | 10.1038/cddis.2013.18 | SDG/關鍵字: | beclin 1; protein mcl 1; pyridine derivative; sc 59; small interfering RNA; sorafenib; STAT3 protein; unclassified drug; article; autophagy; cancer cell culture; carcinoma cell; cell activity; cell death; cell viability; chronotherapy; controlled study; dose response; down regulation; human; human cell; in vivo study; liver cell carcinoma; priority journal; protein expression; tumor growth |
顯示於: | 醫學系 |
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