Radiation therapy is a major treatment for most malignant tumors, and development of new therapeutic strategies is a key challenge to overcome tumor radio-resistance. In this regard, constitutive activation of the phosphatidylinositol 3-kinase (PI3K) survival pathway and tumor cell senescence are two events critically involved in the chemo-resistance and radio-resistance of glioblastomas. In this study we demonstrated that the immunosuppressant FTY720, a PP2A activator, down regulated the PI3K-Akt pathway through inhibition of PP2A-dependant Akt-phosphorylation (ser473), and inhibited the survival and proliferation of human radio-resistant U87G and SF763 glioblastoma cell lines. Interestingly, FTY720 also inhibited the proliferation of U87G after X-irradiation and in contrast to SF763, induced acidic β-gal, a well-characterized senescence marker. Altogether our results indicate that FTY720 could be clinically evaluated as a potential powerful therapeutic tool against human PI3K-dependent and radio-resistant glioblastoma that express the SA-β-beta-gal senescence biomarker.