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

Journal
Oncotarget
Journal Volume
8
Journal Issue
39
Pages
65077-65089
Date Issued
2017
Author(s)
Hu M.-H.
Chen L.-J.
Chen Y.-L.
Tsai M.-S.
Shiau C.-W.
Chao T.-I.
Liu C.-Y.
JIA-HORNG KAO  
Chen K.-F.
DOI
10.18632/oncotarget.17779
URI
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85020407244&doi=10.18632%2foncotarget.17779&partnerID=40&md5=a4355444b818b0559c59e4241a13061f
https://scholars.lib.ntu.edu.tw/handle/123456789/581889
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 autoinhibition. Deletion of the N-SH2 domain (dN1) or point mutation (D61A) of SHP-1 counteracted the effect of SC-43-induced SHP-1 phosphatase activation and antiproliferation ability in CCA cells. In vivo assay revealed that SC-43 exhibited xenograft tumor growth inhibition, p-STAT3 reduction and SHP-1 activity elevation. In conclusion, SC-43 induced apoptosis in CCA cells through the SHP-1/STAT3 signaling pathway. ? Hu et al.
Subjects
Cholangiocarcinoma; Inflammatory cancer; SC-43; SHP-1; STAT3
SDGs

[SDGs]SDG3

Other Subjects
cyclin B1; cyclin dependent kinase 1; protein tyrosine phosphatase SHP 1; sc 43; sorafenib; STAT3 protein; unclassified drug; animal experiment; animal model; animal tissue; antiproliferative activity; apoptosis; Article; bile duct carcinoma; cancer inhibition; cell proliferation; cell viability; CGCCA 100 cell line; cholangiocarcinoma cell line; controlled study; down regulation; drug binding; drug mechanism; drug sensitivity; enzyme activation; G2 phase cell cycle checkpoint; HuCCT 1 cell line; human; human cell; human tissue; immunohistochemistry; in vivo study; KKU 100 cell line; male; mouse; nonhuman; point mutation; protein domain; signal transduction; tumor xenograft; Western blotting
Publisher
Impact Journals LLC
Type
journal article

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