The multiple kinase inhibitor dovitinib is currently under clinical 
investigation for hepatocellular carcinoma (HCC). Here, we investigated the 
mechanistic basis for the effects of dovitinib in HCCs. Dovitinib showed 
significant antitumor activity in HCC cell lines PLC5, Hep3B, Sk-Hep1, and 
Huh-7. Dovitinib downregulated phospho-STAT3 (p-STAT3) at tyrosine 705 and 
subsequently reduced the levels of expression of STAT3-related proteins Mcl-1, 
survivin, and cyclin D1 in a time-dependent manner. Ectopic expression of STAT3 
abolished the apoptotic effect of dovitinib, indicating that STAT3 is 
indispensable in mediating the effect of dovitinib in HCC. SHP-1 inhibitor 
reversed downregulation of p-STAT3 and apoptosis induced by dovitinib, and 
silencing of SHP-1 by RNA interference abolished the effects of dovitinib on 
p-STAT3, indicating that SHP-1, a protein tyrosine phosphatase, mediates the 
effects of dovitinib. Notably, dovitinib increased SHP-1 activity in HCC cells. 
Incubation of dovitinib with pure SHP-1 protein enhanced its phosphatase 
activity, indicating that dovitinib upregulates the activity of SHP-1 via direct 
interactions. In addition, dovitinib induced apoptosis in two 
sorafenib-resistant cell lines through inhibition of STAT3, and 
sorafenib-resistant cells showed significant activation of STAT3, suggesting 
that targeting STAT3 may be a useful approach to overcome drug resistance in 
HCC. Finally, in vivo, dovitinib significantly suppressed growth of both Huh-7 
and PLC5 xenograft tumors and downregulated p-STAT3 by increasing SHP-1 
activity. In conclusion, dovitinib induces significant apoptosis in HCC cells 
and sorafenib-resistant cells via SHP-1-mediated inhibition of STAT3.