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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• 作者：Kuen-Feng Chen^a ; ^b ; ^{kfchen1970@ntu.edu.tw} ; Hui-Ling Chen^a ; ^b ; ^{r96441016@ntu.edu.tw} ; Chun-Yu Liu^d ; ^{liuchunyu_tw@yahoo.com.tw} ; Wei-Tien Tai^a ; ^b ; ^{aces0125@hotmail.com} ; Kimihisa Ichikawa^e ; ^{ichikawa.kimihisa.z5@daiichisankyo.co.jp} ; Pei-Jer Chen^a ; ^{peijerchen@ntu.edu.tw} ; Ann-Lii Cheng^b ; ^c ; ^{alcheng@ntu.edu.tw}
• 关键词：HCC ; hepatocellular carcinoma ; TRAIL ; tumor necrosis factor-related apoptosis-inducing ligand ; STAT3 ; signal transducers and activators of transcription 3 ; FADD ; fas associated protein with death domain ; c-FLIP ; cellular FLICE-inhibitory protein ; PARP ; po
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 出版时间：15 March 2012
• 年：2012
• 卷：83
• 期：6
• 页码：769-777
• 全文大小：1040 K

文摘

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.