Sorafenib Overcomes TRAIL Resistance of Hepatocellular Carcinoma Cells through the Inhibition of STAT3
Sorafenib Overcomes TRAIL Resistance of Hepatocellular Carcinoma Cells through the Inhibition of STAT3
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DOI：
10.1158/1078-0432.ccr-09-3389
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发表时间：
2010-11-01
影响因子：
11.5
通讯作者：
Cheng, Ann-Lii
中科院分区：
文献类型：
--
作者：
Chen, Kuen-Feng;Tai, Wei-Tien;Cheng, Ann-Lii
目的：重组肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种很有前途的抗肿瘤药物。然而，许多肝细胞癌（HCC）细胞显示出对TRAIL诱导的凋亡的抗性。在这里，我们报告说，索拉非尼提高抗肿瘤作用的TRAIL相关药物在耐药hcch.Experimental设计：肝癌细胞系（PLC 5，Huh-7，Hep 3B，和Sk-Hep 1）与索拉非尼和/或TRAIL相关的药物（TRAIL或LBY 135）和分析的凋亡和信号转导。体内疗效测定在裸鼠与PLC 5异种transplants.Results：索拉非尼，唯一批准的药物HCC，敏感性耐药HCC细胞的激动剂DR 5抗体（LBY 135）和TRAIL诱导凋亡的TRAIL耐药HCC细胞。我们发现STAT 3在介导TRAIL致敏中起重要作用。我们的数据表明，索拉非尼下调磷酸化STAT 3（pSTAT 3），并随后降低STAT 3相关蛋白（Mcl-1，生存素，和细胞周期蛋白D1）的表达水平，在TRAIL处理的肝癌细胞中的剂量和时间依赖性的方式。通过RNA干扰敲低STAT 3克服了肝癌细胞中对TRAIL的凋亡抗性，并且肝癌细胞中STAT 3的异位表达消除了索拉非尼的TRAIL增敏作用。此外，SHP-1抑制剂逆转了索拉非尼诱导的pSTAT 3下调和细胞凋亡，通过RNA干扰沉默SHP-1消除了索拉非尼对pSTAT 3的影响。值得注意的是，索拉非尼增加PLC 5细胞中的SHP-1活性。最后，索拉非尼加上LBY 135显着抑制PLC 5异种移植tumor growth.Conclusions：索拉非尼敏感性肝癌细胞TRAIL诱导的凋亡在临床可达到的浓度，这种效果是通过抑制STAT 3介导的。临床癌症研究; 16（21）; 5189-99。（C）2010年AACR。
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. Clin Cancer Res; 16(21); 5189-99. (C)2010 AACR.