EXTH-21. FKBP38 REGULATES SELF-RENEWAL AND SURVIVAL OF GBM NEUROSPHERES

Abstract

Abstract 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. The 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 and autophagy. In this study, we tested the role of FKBP38 in GBM tumor biology. Expression of FKBP38 is upregulated in the patient-derived primary GBM neurospheres (GBMNS) 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 implying that FKBP38 regulates the self-renewal of GBMNS. Also, the transient knockdown of FKBP38 increased the LC3-II/I ratio suggesting the induction of autophagy with the depletion of FKBP38. Further investigation showed that the negative regulation of autophagy by FKBP38 in GBMNS is mediated through the JNK/C-Jun-PTEN-AKT pathway. In vivo, FKBP38 depletion significantly extended the survival of tumor-bearing mice. Overall, our results suggest targeting FKBP38 imparts an anti-GBM effect by inducing apoptosis and autophagy and thus can be a potential therapeutic target for GBM therapy.