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

ABSTRACT:

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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 p

SUBMITTER: Blechacz BR 

PROVIDER: S-EPMC2891152 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature