C. Liu, W. He, M. Jin, H. Li, H. Xu, H. Liu, K. Yang, T. Zhang, G. Wu and J. Ren Pages 663 - 673 ( 11 )
Glioblastoma multiforme (GBM) is the most lethal brain tumor and notorious for its resistance to ionizing radiation (IR). Recent evidence suggests that one possible mechanism that enables resistance to IR and protects cells against therapeutic stress is cellular autophagy. The molecular basis for this pro-survival function, however, remains elusive. Herein, we report a molecular mechanism by which IR-induced autophagy accelerates the repair of DNA double-strand breaks (DSB). We demonstrate that IR induces the accumulation of autophagosomes, which is accompanied by elevated expression of autophagyrelated genes beclin-1, atg5, atg7, and atg12. Beclin-1 knockdown impaired the induction of IR-mediated autophagy and significantly sensitized glioma cells to radiation therapy in vitro and in vivo. Furthermore, our data is the first to demonstrate that the radiosensitizing effect of beclin-1 knockdown may result from the disruption of nuclear translocation and DNA binding activity of Ku proteins and consequent attenuation of DSB repair. Our findings help advance our understanding of the molecular mechanisms underlying IR-induced autophagy and provide a promising adjunctive therapeutic strategy for the radiosensitization of malignant glioma.
Autophagy, beclin-1, DNA-PK, DSB repair, glioblastoma, radiation.
Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 156 Wujiadun Road, Wuhan 430022, P.R. China