Taken together, our results suggest that the PI3K/Akt/FOXO3a/Bim axis might constitute a signaling cascade that mediates the anti-apoptotic activity of SPHK1 in glioma cells and thereby play an essential role in the development and progression of glioma, as well as in its insensitivity to pro-apoptotic therapies. Here, FOXO3 is linked to central nervous system cancer.