Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3
Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3
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DOI：
10.1016/j.bcp.2011.12.035
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发表时间：
2012-03-15
影响因子：
5.8
通讯作者：
Cheng, Ann-Lii
中科院分区：
文献类型：
--
作者：
Chen, Kuen-Feng;Chen, Hui-Ling;Cheng, Ann-Lii
肝细胞癌(HCC)往往对重组肿瘤坏死因子相关的凋亡诱导配体(TRAIL)诱导的细胞凋亡表现出抵抗。多重酪氨酸激酶抑制剂多维替尼和人源化抗人死亡受体(DRS)激动型抗体tigatuzumab均在肝细胞癌的临床研究中。在这里，我们报告多维替尼通过抑制信号转导和转录激活因子3(STAT3)使耐药的肝癌细胞对TRAIL和tigatuzumab诱导的细胞凋亡敏感。我们的数据表明，肝癌细胞对TRAIL和tigatuzumab诱导的细胞凋亡表现出显著的抵抗力。联合应用多维替尼和替加妥珠单抗可恢复肝癌细胞对TRAIL和替加妥珠单抗诱导的细胞凋亡的敏感性。在TRAIL处理的肝癌细胞中，多维替尼下调磷酸化STAT3(Tyr705)(p-STAT3)，并随后降低STAT3调节的蛋白Mcl-1、Survivin和Cylcin D1的蛋白水平。RNA干扰下调STAT3基因可克服肝癌细胞对TRAIL诱导的凋亡抵抗，且STAT3在肝癌细胞中的异位表达可消除多维替尼对TRAIL诱导的细胞凋亡的增敏作用。重要的是，RNA干扰沉默SHP-1降低了多维替尼和TRAIL对p-STAT3和细胞凋亡的影响，而TRAIL和多维替尼联合处理则增加了SHP-1的活性。此外，在体内，tigatuzumab和dovitinib联合使用可抑制Huh-7移植瘤的生长。总之，多维替尼通过一种新的机制使耐药的肝癌细胞对TRAIL和tigatuzumab诱导的凋亡敏感：SHP-1依赖的STAT3抑制。(C)2011 Elsevier Inc.保留所有权利。
Hepatocellular carcinoma (HCC) often displays resistance to recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Dovitinib, a multiple tyrosine kinase inhibitor, and tigatuzumab, a novel humanized anti-human death receptors (DRS)agonistic antibody, are both under clinical investigations in HCC. Here, we report that dovitinib sensitizes resistant HCC cells to TRAIL- and tigatuzumab-induced apoptosis through inhibition of signal transducers and activators of transcription 3 (STAT3). Our data indicate that HCC cells showed significant resistance to TRAIL- and tigatuzumab-induced apoptosis. The combination of dovitinib and tigatuzumab restored the sensitivity of HCC cells to TRAIL- and tigatuzumab-induced apoptosis. Dovitinib down-regulated phospho-STAT3 (Tyr705) (p-STAT3) and subsequently reduced the protein levels of STAT3-regulated proteins, Mcl-1, survivin and cylcin D1, 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 sensitizing effect of dovitinib on TRAIL-induced apoptosis. Importantly, silencing SHP-1 by RNA-interference reduced the effects of dovitinib and TRAIL on p-STAT3 and apoptosis, whereas co-treatment of TRAIL and dovitinib increased the activity of SHP-1. Moreover, in vivo the combination of tigatuzumab and dovitinib inhibited Huh-7 xenograft tumor growth. In conclusion, dovitinib sensitizes resistant HCC cells to TRAIL- and tigatuzumab-induced apoptosis through a novel machinery: SHP-1 dependent STAT3 inhibition. (C) 2011 Elsevier Inc. All rights reserved.