https://scholars.lib.ntu.edu.tw/handle/123456789/553856
標題: | Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3 | 作者: | Chen K.-F. Tai W.-T. TSUNG-HAO LIU HSIANG-PO HUANG Lin Y.-C. Shiau C.-W. Li P.-K. PEI-JER CHEN ANN-LII CHENG |
公開日期: | 2010 | 出版社: | American Association for Cancer Research Inc. | 卷: | 16 | 期: | 21 | 起(迄)頁: | 5189-5199 | 來源出版物: | Clinical Cancer Research | 摘要: | Purpose: Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, many hepatocellular carcinoma (HCC) cells show resistance to TRAIL-induced apoptosis. Here, we report that sorafenib improves the antitumor effect of TRAIL-related agents in resistant HCC. Experimental Design: HCC cell lines (PLC5, Huh-7, Hep3B, and Sk-Hep1) were treated with sorafenib and/or TRAIL-related agents (TRAIL or LBY135) and analyzed in terms of apoptosis and signal transduction. In vivo efficacy was determined in nude mice with PLC5 xenografts. Results: Sorafenib, the only approved drug for HCC, sensitizes resistant HCC cells to an agonistic DR5 antibody (LBY135) and TRAIL-induced apoptosis in TRAIL-resistant HCC cells. We found that STAT3 played a significant role in mediating TRAIL sensitization. Our data showed that sorafenib downregulated phospho-STAT3 (pSTAT3) and subsequently reduced the expression levels of STAT3-related proteins (Mcl-1, survivin, and cyclin D1) in a dose- and time-dependent manner in TRAIL-treated HCC cells. Knockdown of STAT3 by RNA interference overcame apoptotic resistance to TRAIL in HCC cells, and ectopic expression of STAT3 in HCC cells abolished the TRAIL-sensitizing effect of sorafenib. Moreover, SHP-1 inhibitor reversed downregulation of pSTAT3 and apoptosis induced by sorafenib, and silencing of SHP-1 by RNA interference abolished the effects of sorafenib on pSTAT3. Notably, sorafenib increased SHP-1 activity in PLC5 cells. Finally, sorafenib plus LBY135 significantly suppressed PLC5 xenograft tumor growth. Conclusions: Sorafenib sensitizes resistantHCCcells to TRAIL-induced apoptosis at clinical achievable concentrations, and this effect is mediated via the inhibition of STAT3. ?2010 AACR. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84984559474&doi=10.1158%2f1078-0432.CCR-09-3389&partnerID=40&md5=a08d2106f452b93c9af3cb5b856dfae8 https://scholars.lib.ntu.edu.tw/handle/123456789/553856 |
ISSN: | 1078-0432 | DOI: | 10.1158/1078-0432.CCR-09-3389 | SDG/關鍵字: | actin; antineoplastic agent; cyclin D1; death receptor 4; death receptor 5; Fas associated death domain protein; FLICE inhibitory protein; lby 135; protein mcl 1; recombinant tumor necrosis factor related apoptosis inducing ligand; sorafenib; STAT3 protein; survivin; unclassified drug; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; article; cancer growth; concentration response; controlled study; down regulation; drug efficacy; drug mechanism; drug potentiation; human; human cell; in vivo study; liver cell carcinoma; mouse; nonhuman; priority journal; RNA interference; signal transduction |
顯示於: | 醫學院附設醫院 (臺大醫院) |
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