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PMID: 19821497 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Sorafenib inhibits signal transducer and activator of transcription-3 signaling in cholangiocarcinoma cells by activating the phosphatase shatterproof 2.

Hepatology (Baltimore, Md.) ·Vol. 50 ·No. 6 ·2009-12-00 ·Pages 1861-70

Blechacz BR, Smoot RL, Bronk SF, Werneburg NW, Sirica AE, Gores GJ

Abstract

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. 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.

MeSH Terms
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 Niacinamide/analogs & derivatives Phenylurea Compounds 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 Sorafenib Tyrosine/metabolism
Chemicals
Benzenesulfonates Phenylurea Compounds Protein Kinase Inhibitors Pyridines STAT3 Transcription Factor STAT3 protein, human Niacinamide Tyrosine Sorafenib Protein Tyrosine Phosphatase, Non-Receptor Type 11
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Blechacz Boris R A
Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Smoot Rory L
Bronk Steven F
Werneburg Nathan W
Sirica Alphonse E
Gores Gregory J
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Article Info
Journal
Hepatology (Baltimore, Md.)
Abbr.
Hepatology
ISSN
1527-3350
DOI
10.1002/hep.23214
Published
2009-12-00
Pages
1861-70
Language
English
Region
United States
NLM ID
8302946
PMCID
PMC2891152
Subset
IM
Grants
NCI NIH HHS · R01 CA083650-10 · United States
NCI NIH HHS · R01 CA 39225 · United States
NCI NIH HHS · R01 CA 83650 · United States
NIDDK NIH HHS · R01 DK059427 · United States
NIDDK NIH HHS · R56 DK059427 · United States
NCI NIH HHS · R01 CA083650 · United States
NIDDK NIH HHS · DK84567 · United States
NIDDK NIH HHS · R56 DK059427-06 · United States
NIDDK NIH HHS · R01 DK059427-11 · United States
NCI NIH HHS · R01 CA039225 · United States
NIDDK NIH HHS · DK59427 · United States
NIDDK NIH HHS · P30 DK084567 · United States
NCI NIH HHS · R01 CA039225-24 · United States
External Links
PubMed source DOI: 10.1002/hep.23214 PMC Full Text View journal details
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