Targeting SHP-1-STAT3 signaling: A promising therapeutic approach for the treatment of cholangiocarcinoma
- Oncotarget. 2017 May 10;8(39):65077-65089. doi: 10.18632/oncotarget.17779.
- 1. Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
- 2. Division of Hematology and Oncology, Department of Medicine, Cardinal Tien Hospital, New Taipei City, Taiwan.
- 3. School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
- 4. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
- 5. Department of Pathology, Cardinal Tien Hospital, New Taipei City, Taiwan.
- 6. Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
- 7. Transplant Medicine and Surgery Research Centre, Changhua Christian Hospital, Changhua, Taiwan.
- 8. Department of Oncology, Taipei Veterans General Hospital, Taipei City, Taiwan.
- 9. School of Medicine, National Yang-Ming University, Taipei, Taiwan.
- 10. Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
- 11. National Taiwan University College of Medicine, Taipei, Taiwan.
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.