PTEN- and p53-Mediated Apoptosis and Cell Cycle Arrest by FTY720 in Gastric Cancer Cells and Nude Mice

FTY720, a new immunosuppressant, derived from ISP-1, has been studied for its putative anti-cancer properties in the recent years. In tins study, we have reported that FTY720 greatly inhibited gastric cancer cell proliferation for the first time, and found tins effect was associated with G1 phase cell cycle arrest and apoptosis. Results from our Western blotting and Real-time PCR showed that FTY720 induced obvious PTEN expression in a p53-independent way, consistent with a substantial decrease in p-Akt and MDM2 FTY720 dramatically increased the expression of Cip/p21, p27. and BH3-only proteins through the accumulation of p53 by PTEN-mediated inhibition of the PI3K/Akt/MDM2 signaling. Suppression of PTEN expression with siRNA significantly reduced the p53 and 1)21 levels and activated Akt, resulting in decreased apoptosis and increased cell survival. Furthermore, we have observed an additive effect of FTY720 in killing gastric cancer cells when in combination with Cisplatin, partly through PTEN-mediated Akt/MDM2 inhibition In vivo study has also shown that tumor growth was significantly suppressed after FTY720 treatment In conclusion, our results suggest that FTY720 induces a significant increase of PIEN, which inhibits p-Akt and MDM2, and then increases the level of p53, thereby inducing G I phase arrest and apoptosis We have characterized a novel immunosuppressant, for the first time, which shows potential anti-tumor effects on gastric cancer by FEN activation through p53-independent mechanism, especially in combination with Cisplatin. This PTEN target-based therapy is worth further investigation and warrants clinical evaluation. J. Cell. Biochem. 111: 218-228, 2010. (C) 2010 Wiley-Liss, Inc