Targeting SHP-1-STAT3 signaling: A promising therapeutic approach for the treatment of cholangiocarcinoma.

ABSTRACT: Sorafenib is a multiple kinase inhibitor which targets Raf kinases, VEGFR, and PDGFR and is approved for the treatment of hepatocellular carcinoma (HCC). Previously, we found that p-STAT3 is a major target of SC-43, a sorafenib derivative. In this study, we report that SC-43-induced apoptosis in cholangiocarcinoma (CCA) via a novel mechanism. Three CCA cell lines (HuCCT-1, KKU-100 and CGCCA) were treated with SC-43 to determine their sensitivity to SC-43-induced cell death and apoptosis. We found that SC-43 activated SH2 domain-containing phosphatase 1 (SHP-1) activity, leading to p-STAT3 and downstream cyclin B1 and Cdc2 downregulation, which induced G2-M arrest and apoptotic cell death. Importantly, SC-43 augmented SHP-1 activity by direct binding to N-SH2 and relief of its autoinhibitio

SUBMITTER: Hu MH 

PROVIDER: S-EPMC5630313 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature