| Sorafenib inhibits signal transducer and activator of transcription-3 signaling in cholangiocarcinoma cells by activating the phosphatase shatterproof 2. | |
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MedLine Citation:
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PMID: 19821497 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is one of the key signaling cascades in cholangiocarcinoma (CCA) cells, mediating their resistance to apoptosis. Our aim was to ascertain if sorafenib, a multikinase inhibitor, may also inhibit JAK/STAT signaling and, therefore, be efficacious for CCA. Sorafenib treatment of three human CCA cell lines resulted in Tyr(705) phospho-STAT3 dephosphorylation. Similar results were obtained with the Raf-kinase inhibitor ZM336372, suggesting sorafenib promotes Tyr(705) phospho-STAT3 dephosphorylation by inhibiting Raf-kinase activity. Sorafenib treatment enhanced an activating phosphorylation of the phosphatase SHP2. Consistent with this observation, small interfering RNA-mediated knockdown of phosphatase shatterproof 2 (SHP2) inhibited sorafenib-induced Tyr(705) phospho-STAT3 dephosphorylation. Sorafenib treatment also decreased the expression of Mcl-1 messenger RNA and protein, a STAT3 transcriptional target, as well as sensitizing CCA cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. In an orthotopic, syngeneic CCA model in rats, sorafenib displayed significant tumor suppression resulting in a survival benefit for treated animals. In this in vivo model, sorafenib also decreased tumor Tyr(705) STAT3 phosphorylation and increased tumor cell apoptosis. CONCLUSION: Sorafenib accelerates STAT3 dephosphorylation by stimulating phosphatase SHP2 activity, sensitizes CCA cells to TRAIL-mediated apoptosis, and is therapeutic in a syngeneic rat, orthotopic CCA model that mimics human disease. |
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Authors:
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Boris R A Blechacz; Rory L Smoot; Steven F Bronk; Nathan W Werneburg; Alphonse E Sirica; Gregory J Gores |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 50 ISSN: 1527-3350 ISO Abbreviation: Hepatology Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-11-27 Completed Date: 2009-12-15 Revised Date: 2011-03-01 |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: United States |
Other Details:
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Languages: eng Pagination: 1861-70 Citation Subset: IM |
Affiliation:
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Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects Benzenesulfonates / pharmacology* Bile Duct Neoplasms / drug therapy*, pathology Bile Ducts, Intrahepatic Cell Line, Tumor Cholangiocarcinoma / drug therapy*, pathology Enzyme Activation Humans Male Phosphorylation Protein Kinase Inhibitors / pharmacology* Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism* Pyridines / pharmacology* Rats Rats, Inbred F344 STAT3 Transcription Factor / antagonists & inhibitors*, metabolism Signal Transduction / drug effects* Tyrosine / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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DK59427/DK/NIDDK NIH HHS; DK84567/DK/NIDDK NIH HHS; R01 CA 39225/CA/NCI NIH HHS; R01 CA 83650/CA/NCI NIH HHS; R01 CA039225-24/CA/NCI NIH HHS; R01 CA039225-26/CA/NCI NIH HHS; R01 CA083650-10/CA/NCI NIH HHS; R01 DK059427-11/DK/NIDDK NIH HHS; R56 DK059427-06/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Benzenesulfonates; 0/Protein Kinase Inhibitors; 0/Pyridines; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 0/sorafenib; 55520-40-6/Tyrosine; EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 11 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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