| Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. | |
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MedLine Citation:
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PMID: 20884624 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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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 resistant HCC cells to TRAIL-induced apoptosis at clinical achievable concentrations, and this effect is mediated via the inhibition of STAT3. |
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Authors:
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Kuen-Feng Chen; Wei-Tien Tai; Tsung-Hao Liu; Hsiang-Po Huang; Yu-Chin Lin; Chung-Wai Shiau; Pui-Kai Li; Pei-Jer Chen; Ann-Lii Cheng |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-09-30 |
Journal Detail:
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Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: 16 ISSN: 1078-0432 ISO Abbreviation: Clin. Cancer Res. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-02 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 5189-99 Citation Subset: IM |
Copyright Information:
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©2010 AACR. |
Affiliation:
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Department of Medical Research, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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