Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma
Journal
Journal of Hepatology
Journal Volume
55
Journal Issue
5
Pages
1041-1048
Date Issued
2011
Author(s)
Abstract
Background & Aims: Recently, we reported that sorafenib sensitizes hepatocellular carcinoma (HCC) cells to TRAIL through the inhibition of signal transducer and activator of transcription 3 (STAT3). Here, we report that sorafenib inhibits HCC via a kinase-independent mechanism: SHP-1 dependent STAT3 inactivation. Methods: SC-1 is a sorafenib derivative that closely resembles sorafenib structurally but with no kinase inhibition activity. HCC cell lines (PLC5, Huh-7, Hep3B, and Sk-Hep1) were treated with sorafenib or SC-1 and apoptosis and signal transduction were analyzed. In vivo efficacy was determined in nude mice with Huh-7 xenografts. Results: SC-1 showed similar effects to sorafenib on growth inhibition and apoptosis in all tested HCC cell lines. SC-1 down-regulated phosphorylation of phospho-STAT3 (p-STAT3) at tyrosine 705 in all tested HCC cells. Expression of STAT3-driven genes, including Cyclin D1 and Survivin, was also repressed by SC-1. Luciferase reporter assay confirmed the inhibition of transcriptional activity of STAT3 in both sorafenib-treated and SC-1-treated cells. Ectopic expression of STAT3 in PLC5 cells abolished apoptosis in SC-1-treated cells. Sorafenib and SC-1 up-regulated SHP-1 activity. Knockdown of SHP-1, but not SHP-2 or PTP-1B, by small interference RNA reduced apoptosis induced by SC-1. Finally, SC-1 reduced Huh-7 tumor growth significantly in vivo, which was associated with down-regulation of p-STAT3 and up-regulation of SHP-1 activity. Conclusions: STAT3 is a major kinase-independent target of sorafenib in HCC. ? 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
SDGs
Other Subjects
antineoplastic agent; cyclin D1; drug metabolite; protein tyrosine phosphatase SHP 1; sc 1; small interfering RNA; sorafenib; STAT3 protein; survivin; unclassified drug; animal experiment; animal model; antineoplastic activity; apoptosis; article; cancer inhibition; controlled study; down regulation; drug dose escalation; drug efficacy; drug targeting; enzyme activity; human; human cell; in vivo study; liver cell carcinoma; male; mouse; nonhuman; priority journal; protein expression; protein phosphorylation; signal transduction; structure activity relation; tumor xenograft
Publisher
Elsevier B.V.
Type
journal article