Moesin silencing enhances the radiosensitivity of glioblastoma by inhibiting DNA damage repair via CD44/AKT1 signaling pathway.

The complicated radioresistance remains an intractable cause of treatment failure in glioblastoma (GBM). The cytoskeletal protein moesin (MSN) has been demonstrated to play crucial roles in the initiation and development of various cancers, but its involvement in the radioresistance of malignancies, particularly GBM, remains poorly understood. In this study, we found that MSN expression was significantly elevated in high-grade gliomas and closely correlated with poor clinical outcomes in patients with glioma, including GBM. Moreover, MSN expression was positively associated with the expression of genes implicated in radioresistance of GBM. In vitro experiments revealed that silencing MSN inhibited GBM cell proliferation, promoted apoptosis, and enhanced the radiosensitivity of GBM cells. Furthermore, in vivo studies showed that MSN knockout combined with radiotherapy markedly suppressed tumor growth and prolonged survival in GBM-bearing mice. Mechanistically, MSN inhibition led to reduced expression levels of CD44, AKT1, phosphorylated AKT1 (Ser-473), DNA-PKcs, KU70, and KU80. Collectively, these findings suggest that MSN may serve as a novel and promising therapeutic target for GBM by modulating the CD44/AKT1 signaling pathway to impairing DNA damage repair induced by radiotherapy.