Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma.

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.

• Authors: Wei-Tien Tai, Ann-Lii Cheng, Chung-Wai Shiau, Hsiang-Po Huang, Jui-Wen Huang, Pei-Jer Chen, Kuen-Feng Chen
• Journal: Journal of hepatology (J Hepatol) Vol. 55 Issue 5 Pg. 1041-8 (Nov 2011) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 21354226 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Benzenesulfonates
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Pyridines
• STAT3 Transcription Factor
• Niacinamide
• Sorafenib
• Proto-Oncogene Proteins c-raf
• PTPN6 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 6

Topics

• Animals
• Apoptosis (drug effects)
• Benzenesulfonates (pharmacology)
• Carcinoma, Hepatocellular (drug therapy, enzymology)
• Cell Line, Tumor
• Down-Regulation
• Humans
• Liver Neoplasms (drug therapy, enzymology)
• Mice
• Mice, Nude
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Protein Kinase Inhibitors (pharmacology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 6 (drug effects, metabolism)
• Proto-Oncogene Proteins c-raf (metabolism)
• Pyridines (pharmacology)
• STAT3 Transcription Factor (drug effects, metabolism)
• Signal Transduction (drug effects)
• Sorafenib