Targeting SHP-1-STAT3 signaling: A promising therapeutic approach for the treatment of cholangiocarcinoma
Metrics: PDF 578 views | HTML 1357 views | ?
Ming-Hung Hu3,4,5, Li-Ju Chen1, Yen-Lin Chen7, Ming-Shen Tsai1, Chung-Wai Shiau8, Tzu-I Chao9, Chun-Yu Liu6,10, Jia-Horng Kao3,11 and Kuen-Feng Chen1,2
1Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
2National Taiwan University College of Medicine, Taipei, Taiwan
3Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
4Division of Hematology and Oncology, Department of Medicine, Cardinal Tien Hospital, New Taipei City, Taiwan
5School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
6Department of Oncology, Taipei Veterans General Hospital, Taipei City, Taiwan
7Department of Pathology, Cardinal Tien Hospital, New Taipei City, Taiwan
8Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
9Transplant Medicine and Surgery Research Centre, Changhua Christian Hospital, Changhua, Taiwan
10School of Medicine, National Yang-Ming University, Taipei, Taiwan
11Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
Kuen-Feng Chen, email: firstname.lastname@example.org
Jia-Horng Kao, email: email@example.com
Chun-Yu Liu, email: firstname.lastname@example.org
Keywords: cholangiocarcinoma, SC-43, STAT3, SHP-1, inflammatory cancer
Received: May 09, 2016 Accepted: April 26, 2017 Published: May 10, 2017
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.