Signal transducer and activator of transcription 3 is a major kinase-independent _target of sorafenib in hepatocellular carcinoma
- PMID: 21354226
- DOI: 10.1016/j.jhep.2011.01.047
Signal transducer and activator of transcription 3 is a major kinase-independent _target of sorafenib in hepatocellular carcinoma
Erratum in
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Corrigendum to "Signal transducer and activator of transcription 3 is a major kinase-independent _target of sorafenib in hepatocellular carcinoma".J Hepatol. 2017 Mar;66(3):666-668. doi: 10.1016/j.jhep.2016.12.007. Epub 2017 Jan 6. J Hepatol. 2017. PMID: 28069352 No abstract available.
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.
Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Comment in
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_targeting STAT3 in hepatocellular carcinoma: sorafenib again….J Hepatol. 2011 Nov;55(5):957-9. doi: 10.1016/j.jhep.2011.06.005. Epub 2011 Jun 28. J Hepatol. 2011. PMID: 21718664 No abstract available.
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