1. FTY720 inhibits proliferation and epithelial-mesenchymal transition in cholangiocarcinoma by inactivating STAT3 signaling
- Author
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Shangha Pan, Tongsen Zheng, Dalong Yin, Lianxin Liu, Hongchi Jiang, Jiabei Wang, Yingjian Liang, Zhaoyang Lu, Tiemin Pei, and Ruipeng Song
- Subjects
STAT3 Transcription Factor ,FTY720 ,Cancer Research ,Epithelial-Mesenchymal Transition ,Cell ,Apoptosis ,Cell Cycle Proteins ,Biology ,Cell cycle ,Cholangiocarcinoma ,STAT3 ,Mice ,Sphingosine ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Genetics ,Animals ,Humans ,Epithelial–mesenchymal transition ,Neoplasm Metastasis ,Phosphorylation ,Cell Proliferation ,Dose-Response Relationship, Drug ,Cell growth ,Fingolimod Hydrochloride ,Xenograft Model Antitumor Assays ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,medicine.anatomical_structure ,Bile Ducts, Intrahepatic ,Oncology ,Bile Duct Neoplasms ,Propylene Glycols ,Caspases ,Cancer research ,biology.protein ,Stem cell ,Signal transduction ,Signal Transduction ,Research Article - Abstract
Background Interleukin 6 (IL-6)-mediated signal transducers and activators of transcription 3 (STAT-3) phosphorylation (activation) is aberrantly sustained in cholangiocarcinoma cells resulting in enhanced myeloid cell leukemia 1 (Mcl-1) expression and resistance to apoptosis. FTY720, a new immunosuppressant, derived from ISP-1, has been studied for its putative anti-cancer properties. This study aimed to elucidate the mechanism by which FTY720 mediates antitumor effects in cholangiocarcinoma (CC) cells. Methods Three CC cell lines were examined, QBC939, TFK-1, and HuCCT1. The therapeutic effects of FTY720 were evaluated in vitro and in vivo. Cell proliferation, apoptosis, cell cycle, invasive potential, and epithelial- mesenchy-mal transition (EMT) were examined. Results FTY720 greatly inhibited CC cells proliferation and EMT in vitro and in vivo, and this effect was associated with dephosphorylation of STAT3tyr705. FTY720 induced apoptosis and G1 phase arrest in CC cells, and inhibited invasion of CC cells. Western blot analysis showed that FTY720 induced cleavage of caspases 3, 8 and 9, and of PARP, in a dose-dependent manner, consistent with a substantial decrease in p-STAT3, Bcl-xL, Bcl-2, survivin, cyclin D1, cyclin E, N-cadherin, vimentin, VEGF and TWIST1. In vivo studies showed that tumor growth and metastasis were significantly suppressed after FTY720 treatment. Conclusions These results suggest that FTY720 induces a significant decrease in p-STAT3, which inhibits proliferation and EMT of CC cells, and then induces G1 phase arrest and apoptosis. We have characterized a novel immunosuppressant, which shows potential anti-tumor effects on CC via p-STAT3 inhibition. FTY720 merits further investigation and warrants clinical evaluation. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-783) contains supplementary material, which is available to authorized users.
- Published
- 2014