Chen K.-F.Chen H.-L.Liu C.-Y.Tai W.-T.Ichikawa K.PEI-JER CHENANN-LII CHENG2021-07-032021-07-0320120006-2952https://www.scopus.com/inward/record.uri?eid=2-s2.0-84984550442&doi=10.1016%2fj.bcp.2011.12.035&partnerID=40&md5=a01c892d4d62211aaa585d48d75e45b4https://scholars.lib.ntu.edu.tw/handle/123456789/568491Hepatocellular 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.[SDGs]SDG3cyclin 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 regulationjournal article10.1016/j.bcp.2011.12.0352-s2.0-84984550442