title: Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma.
abstract: OBJECTIVE
  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.affiliation: National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.forename: Hsiang-Po
authors.initials: HP
authors.lastname: Huang
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Huang
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000187:drug effects / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D050796:STAT3 Transcription Factor; D009536:Niacinamide; D000077157:Sorafenib; D019908:Proto-Oncogene Proteins c-raf; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6