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

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

doi:10.18632/oncotarget.17779

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.

Highlights

Cholangiocarcinoma (CCA) is the second most common hepatic malignancy after hepatocellular carcinoma (HCC) and the most common biliary malignancy, accounting for 3% of all gastrointestinal tumors [1]
We found that SC-43 activated Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) activity, leading to p-Signal transducers and activators of transcription 3 (STAT3) and downstream cyclin B1 and Cdc2 downregulation, which induced G2-M arrest and apoptotic cell death
We found that SC-43 induced cancer cell apoptosis through upregulation of SHP-1 and downregulation of phosphorylated STAT3 (p-STAT3), suggesting that SHP-1 is a target of SC-43 [18]

Summary

Introduction

Cholangiocarcinoma (CCA) is the second most common hepatic malignancy after hepatocellular carcinoma (HCC) and the most common biliary malignancy, accounting for 3% of all gastrointestinal tumors [1]. CCAs are epithelial malignancies that arise from cholangiocytes and are characterized by aggressive behavior and advanced clinical stage. The mortality from CCA is still increasing [4]. Not a single www.impactjournals.com/oncotarget targeted agent has been approved for the treatment of CCA. Treatment options for CCA are limited, and cytotoxic chemotherapy remains the only choice for unresectable metastatic CCA. CCA is generally refractory to most chemotherapy, and 5-year survival rate is extremely poor, remaining at 10% [5, 6]. The unmet medical need in patients with CCA remains a great clinical challenge. Owing to the unsatisfactory therapeutic outcomes under the current standard management, development of novel agents for treatment of CCA is undoubtedly an important mission

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