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首页> 外文期刊>Biochemical Pharmacology >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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Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3

机译：多维替尼通过SHP-1依赖性抑制STAT3使肝癌细胞对TRAIL和新型抗DR5抗体tigatuzumab敏感

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摘要

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 receptor 5 (DR5) 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.
机译：肝细胞癌（HCC）通常显示出对重组肿瘤坏死因子相关的凋亡诱导配体（TRAIL）诱导的凋亡的抵抗力。多种酪氨酸激酶抑制剂Dovitinib和新型人源化抗人死亡受体5（DR5）激动剂tigatuzumab均在HCC中进行临床研究。在这里，我们报道dovitinib通过抑制信号转导子和转录激活因子3（STAT3）使抗性HCC细胞对TRAIL和tigatuzumab诱导的凋亡敏感。我们的数据表明，HCC细胞对TRAIL和tigatuzumab诱导的细胞凋亡显示出显着的抗性。 dovitinib和tigatuzumab的组合恢复了HCC细胞对TRAIL和tigatuzumab诱导的细胞凋亡的敏感性。在TRAIL处理的HCC细胞中，Dovitinib下调磷酸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干扰敲低STAT3克服了HCC细胞对TRAIL的凋亡抗性，并且STAT3在HCC细胞中的异位表达消除了dovitinib对TRAIL诱导的细胞凋亡的敏化作用。重要的是，通过RNA干扰使SHP-1沉默可降低dovitinib和TRAIL对p-STAT3和细胞凋亡的影响，而TRAIL和dovitinib的共同治疗可提高SHP-1的活性。此外，在体内替加妥珠单抗和多维替尼的组合抑制了Huh-7异种移植肿瘤的生长。总之，多维替尼通过一种新的机制：SHP-1依赖性STAT3抑制作用，使耐药HCC细胞对TRAIL和tigatuzumab诱导的细胞凋亡敏感。

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