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Abstract
BackgroundInterleukin 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.MethodsThree 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.ResultsFTY720 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.ConclusionsThese 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 materialThe online version of this article (doi:10.1186/1471-2407-14-783) contains supplementary material, which is available to authorized users.
Highlights
Interleukin 6 (IL-6)-mediated signal transducers and activators of transcription 3 (STAT-3) phosphorylation is aberrantly sustained in cholangiocarcinoma cells resulting in enhanced myeloid cell leukemia 1 (Mcl-1) expression and resistance to apoptosis
We investigated the effect of FTY720 on the signal transducer and activator of transcription 3 (STAT3) cell survival pathway and found that STAT3 dephosphorylation plays a central role in cell growth arrest, apoptosis and metastasis upon administration of FTY720 to CC cell lines
FTY720 is a potent anti-CC agent and induces apoptosis in CC cells The in vitro activity of FTY720 against CC cells was evaluated after 24 h of exposure to drug
Summary
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. This study aimed to elucidate the mechanism by which FTY720 mediates antitumor effects in cholangiocarcinoma (CC) cells. Human cholangiocarcinoma (CC) arises from the epithelium of the biliary tree. STAT3 is a transcription factor that is constitutively activated in many types of cancer, contributing to tumor progression via several mechanisms. IL-6–activated STAT3 is crucial for survival of several types of cancer cell, including multiple myeloma, a plasmacytic B-cell malignancy [6,13]. Studies suggest that IL-6/STAT3 signaling is aberrant in human CC cells and CC tissues with prolonged and sustained STAT-3 phosphorylation [14,15]. The mechanisms responsible for this atypical IL-6 signaling response are unclear but of pathophysiological importance
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