Dovitinib Induces Apoptosis and Overcomes Sorafenib Resistance in Hepatocellular Carcinoma through SHP-1–Mediated Inhibition of STAT3

Abstract

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. Mol Cancer Ther; 11(2); 452-63. Ó2011 AACR.

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

“…Moreover, another multikinase inhibitor Dovitinib has been found to induce apoptosis and overcome sorafenib resistance in HCC through SHP-1-mediated inhibition of STAT3 [267]. Additionally, STAT3 inhibitor NSC74859 has been found to be greatly effective in HCC with disrupted TGF-β signaling [6].…”

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

“…STAT3 plays a critical role in transcriptional regulation of genes and is also activated by many cytokines and growth factor receptors, such as PDGFR, fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR) through JAK [25,26] . The negative regulation of STAT3 is mainly executed by suppression of cytokine signaling (SOCS) proteins through JAK and Src-homology protein tyrosine phosphatases (SHPs), such as SHP-1 and SHP-2, and cytokines and growth factor receptors [23] .…”

“…Several studies have also investigated the role of JAK-STAT pathway in the mechanisms of acquired resistance to sorafenib in HCC. Sorafenib-resistant HCC cells express higher levels of p-STAT3, p-JAK1 and p-JAK2, but lower levels of SHP-1 and p-SHP-1, indicating that the JAK-STAT pathway participates in the acquired resistance to sorafenib in HCC [26] . Interestingly, dovitinib, another multikinase inhibitor targeting VEGFR, FGFR and c-KIT and regulating the JAK-STAT pathway, could reverse the acquired resistance to sorafenib by directly activating SHP-1 and thus downregulating p-STAT3 [26] .…”

“…Sorafenib-resistant HCC cells express higher levels of p-STAT3, p-JAK1 and p-JAK2, but lower levels of SHP-1 and p-SHP-1, indicating that the JAK-STAT pathway participates in the acquired resistance to sorafenib in HCC [26] . Interestingly, dovitinib, another multikinase inhibitor targeting VEGFR, FGFR and c-KIT and regulating the JAK-STAT pathway, could reverse the acquired resistance to sorafenib by directly activating SHP-1 and thus downregulating p-STAT3 [26] . Inhibition of SHP-1 or gene knockdown of SHP-1 blocked the effect of dovitinib, indicating that the SHP-1-activating agent may provide second-line treatment after the failure of sorafenib therapy [30] .…”

MicroRNA-486-5p enhances hepatocellular carcinoma tumor suppression through repression of IGF-1R and its downstream mTOR, STAT3 and c-Myc

“…Compensatory activation of associated downstream signaling pathways, including the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and RAS/RAF/mitogen-activated protein kinase (MAPK) signaling cascades ( Fig. 1), emerged as a critical mechanism of drug resistance in HCC cells (9)(10)(11). Hence, targeting a single point in this pivotal signaling pathway was found to induce compensatory up-and/or downstream activation, resulting in drug resistance (12,13).…”