Inhibition of Stat3 activity by YC-1 enhances chemo-sensitivity in hepatocellular carcinoma

The present study investigated the effect of YC-1, a novel anti-cancer agent, on the chemo-sensitivity of hepatocellular carcinoma (HCC). YC-1 was administered with chemo-cytotoxic drug, cisplatin, both in vitro and in vivo. YC-1 alone down-regulated the expression of phosphorylated form of signal transducers and activators of transcription 3 (P-Stat3[705]), a key mediator in chemo-resistance. When combined with cisplatin, YC-1 further promoted tumor cell apoptosis, decreased the expression of P-Stat3(705), Bcl-xL, CyclinD1 and survivin, and induced the cleavage of caspase 9 and PARP. Over-expression of Stat3 reversed YC-1 induced cell death. YC-1 inhibited Stat3 activity by enhancing the polyubiquitination of P-Stat3(705) induced by cisplatin. In the in vivo setting, YC-1 combined with cisplatin remarkably suppressed tumor growth in a HCC xenograft model, and this effect was also accompanied by YC-1 mediated down-regulation of P-Stat3(705), Bcl-xL, Cyclin D1 and survivin, and induction of cleaved caspase...