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

Ming Hung Hu, Li Ju Chen, Yen Lin Chen, Ming Shen Tsai, Chung Wai Shiau, Tzu I. Chao, Chun Yu Liu, Jia Horng Kao, Kuen Feng Chen

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)65077-65089
Number of pages13
JournalOncotarget
Volume8
Issue number39
DOIs
Publication statusPublished - 2017
Externally publishedYes

Keywords

  • Cholangiocarcinoma
  • Inflammatory cancer
  • SC-43
  • SHP-1
  • STAT3

ASJC Scopus subject areas

  • Oncology

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