title: FTY720 inhibits proliferation and epithelial-mesenchymal transition in cholangiocarcinoma by inactivating STAT3 signaling.
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.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Lu
authors.forename: Jiabei
authors.initials: J
authors.lastname: Wang
authors.forename: Tongsen
authors.initials: T
authors.lastname: Zheng
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Liang
authors.forename: Dalong
authors.initials: D
authors.lastname: Yin
authors.forename: Ruipeng
authors.initials: R
authors.lastname: Song
authors.forename: Tiemin
authors.initials: T
authors.lastname: Pei
authors.forename: Shangha
authors.initials: S
authors.lastname: Pan
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, No, 23 Youzheng Street, Heilongjiang Province, Harbin 150001, China. liulianxin@ems.hrbmu.edu.cn.
authors.forename: Lianxin
authors.initials: L
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D000068876:Fingolimod Hydrochloride; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D011409:Propylene Glycols / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D011409:Propylene Glycols; D050796:STAT3 Transcription Factor; D020169:Caspases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine