Oncotarget

Research Papers:

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 _

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Abstract

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

Correspondence to:

Kuen-Feng Chen, email: kfchen1970@ntu.edu.tw

Jia-Horng Kao, email: kaojh@ntu.edu.tw

Chun-Yu Liu, email: cyliu3@vghtpe.gov.tw

Keywords: cholangiocarcinoma, SC-43, STAT3, SHP-1, inflammatory cancer

Received: May 09, 2016     Accepted: April 26, 2017     Published: May 10, 2017

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.

Author Information

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
Primary Contact  _


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