Interestingly, the expression of SIRT6 was reduced after FKHRL1 knockdown, while its expression was upregulated when FKHRL1 was overexpressed in human U251 GBM cell line.
In addition, we found that specific FOXO3a activation recapitulated the molecular effects of EGFR inhibition, and that the FOXO3a activator trifluoperazine, a FDA-approved antipsychotic agent, reduced GBM cell growth.
MicroRNA-370 suppresses the progression and proliferation of human astrocytoma and glioblastoma by negatively regulating β-catenin and causing activation of FOXO3a.
Taken together, we propose ICA II as a potential novel anti-GBM candidate with a mechanism of inhibiting cell proliferation and inducing apoptosis through suppressing Akt activation and potentiating FOXO3a activity.
These findings suggest that high FoxO3a expression is associated with glioblastoma progression and that FoxO3a independently indicates poor prognosis in patients.
This delayed apoptotic event was preceded by FoxO3A nuclear accumulation, FoxO3A phosphorylation on serine residue 413, its elevated transcriptional activity and expression of FoxO-dependent apoptotic protein, Bim. siRNA-mediated inhibition of FoxO3A attenuated fenofibrate-induced apoptosis, indicating a direct involvement of this transcription factor in the fenofibrate action against glioblastoma.