https://scholars.lib.ntu.edu.tw/handle/123456789/568491
標題: | Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3 | 作者: | Chen K.-F. Chen H.-L. Liu C.-Y. Tai W.-T. Ichikawa K. PEI-JER CHEN ANN-LII CHENG |
公開日期: | 2012 | 出版社: | Elsevier Inc. | 卷: | 83 | 期: | 6 | 起(迄)頁: | 769-777 | 來源出版物: | Biochemical Pharmacology | 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. ? 2011 Elsevier Inc. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84984550442&doi=10.1016%2fj.bcp.2011.12.035&partnerID=40&md5=a01c892d4d62211aaa585d48d75e45b4 https://scholars.lib.ntu.edu.tw/handle/123456789/568491 |
ISSN: | 0006-2952 | DOI: | 10.1016/j.bcp.2011.12.035 | SDG/關鍵字: | cyclin D1; dovitinib; protein mcl 1; protein tyrosine phosphatase SHP 1; recombinant tumor necrosis factor related apoptosis inducing ligand; small interfering RNA; STAT3 protein; survivin; tigatuzumab; animal experiment; animal model; antineoplastic activity; apoptosis; article; cancer cell destruction; cancer inhibition; cancer resistance; carcinoma cell; chemosensitization; controlled study; down regulation; enzyme activation; gene silencing; human; human cell; in vivo study; liver cell carcinoma; male; mouse; nonhuman; priority journal; protein cleavage; protein content; protein phosphorylation; RNA interference; transcription regulation |
顯示於: | 臨床醫學研究所 |
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