Introduction: Glioblastoma (GBM) is the most common malignant primary brain tumor. The outcome is dismal, despite the multimodal therapeutic approach that includes surgical resection followed by radiation and chemotherapy. A quest for novel therapeutic targets to treat GBM is underway. FKBP38, a member of the immunophilin family of proteins, is a multidomain protein that plays an important role in the regulation of cellular functions including apoptosis. In this study, we tested the role of FKBP38 in GBM tumor biology.
Methods: Patient-derived primary GBM neurosphere (GBMNS) models were transfected with scrambled or target-specific FKBP38 siRNA and were subjected to viability assay, caspase 3/7 activity assay, neurosphere formation assay, cell cycle, and western blot analysis. The intracranial GBM mouse model was used for in vivo studies.
Results: Expression of FKBP38 is upregulated in the patient-derived primary GBM neurospheres compared to normal human astrocytes. Attenuation of FKBP38 expression decreased the viability of GBMNS and increased the caspase 3/7 activity indicating that FKBP38 is required for the survival of GBMNS. Further, the depletion of FKBP38 significantly reduced the number of neurospheres that were formed suggesting that FKBP38 regulates the self-renewal of GBMNS. In vivo, FKBP38-depletion significantly extended the survival of tumor-bearing mice.
Conclusion : Overall, our results suggest targeting FKBP38 imparts an anti-GBM effect by inducing apoptosis and thus can be a potential therapeutic target for GBM therapy.
