FTY720, A Synthetic Compound From Isaria Sinclairii, Inhibits Proliferation And Induces Apoptosis In Pancreatic Cancer Cells

Objectives:FTY720, a synthetic compound produced by modification of a metabolite from Isaria sinclairii, is known as a unique immunosuppressive agent that exerts its activity by inducing apoptosis of lymphocytes. Additionally, it has been found that FTY720 has inhibitory effects on various cancer growth and metastasis. To investigate its effect on the growth and metastasis of pancreatic cancer, FTY720 was used to treat three pancreatic cancer cell lines (BxPC-3, AsPC-1, PANC-1).Methods:The pancreatic cancer cell lines (BxPC-3, AsPC-1, PANC-1) were treated with FTY720 at various concentrations in present study. The MTT assay was used to assess cytostatic activity induced by FTY720. Flow cytometry was adopted to evaluate thecell apoptosis after FTY720 treatment. Three-dimensional (3D) Matrigel assay was used to investigate the colony formation ability of pancreatic cells after FTY720 treatment. The wound closure and cell invasion assay were employed to observe the cell migration and invasion ability. Western blotting was used to demonstrate expression levels of involved protein such as phospho-Akt, Akt ,Bcl-2, caspase-9 and pro-caspase-3.All the detection items in this study were repeated at least 3 times. Statistical analysis was done using SPSS software. The data was expressed as mean ± SD and the statistical significance of the differences between control and FTY720-treated cells was determined by a two-tailed Student's t test. The Spearman correlation test was used to analyze the correlation between reagents' concentrations and inhibition rates. P-value <0.05 was considered as significant.Results:The MTT assay indicated that the growth of pancreatic cancer cells could be inhibited by FTY720 at various concentrations between 0-17 μM in a dose-dependent manner, which was also confirmed by flow cytometry. The wound closure assay, 3D Matrigel assay and cell invasion assay all showed the FTY720 significantly suppressed migration, colony formation and invasion ability of cancer cells at concentrations from 5 μM to 17 μM. After FTY720 treatment, the phospho-Akt, bcl-2, pro-caspase-3 expression were down regulated while the caspase-9 protein expression was increased. In conclusion, FTY720 can inhibit the growth, migration and invasion of pancreatic cancer cells. Our study provides a preclinical support for chemotherapeutic approach with FTY720 for the treatment of pancreatic cancer.Conclusions:In this study, the apoptosis-induced effects of FTY720 on human pancreatic cancer cell lines were analyzed. The FTY720 can inhibit growth, migration and invasion, also can induce apoptosis of pancreatic cancer cells. The findings presented here reveal that FTY720 induced marked apoptosis in pancreatic cancer cells mainly by influencing Akt and several Bcl-2 family members, which would trigger caspases-induced apoptosis. These data provide preclinical support for chemotherapeutic approach with FTY720 for the treatment of pancreatic cancer. All these results indicate that FTY720 may represent a novel class of chemotherapeutic agent for pancreatic cancer.