Autophagic flux response and glioblastoma sensitivity to radiation

Abstract

Objective:Glioblastoma is the most common primary brain tumor in adults and one of the most lethal human tumors. It constitutes a unique non-metastasizing human tumor model with high resistance to radiotherapy and chemotherapy. The current study investigates the association between autophagic flux and glioblastoma cell resistance.Methods:The expression kinetics of autophagy- and lysosome-related proteins following exposure of two glioblastoma cell lines (T98 and U87) to clinically relevant radiation doses was examined. Then, the response of cells resistant to radiotherapy and chemotherapy was investigated after silencing of LC3A, LC3B, and TFEB genes in vitro and in vivo. Results:Following irradiation with 4 Gy, the relatively radioresistant T98 cells exhibited enhanced autophagic flux. The more radiosensitive U87 cell line suffered a blockage of autophagic flux. Silencing of LC3A, LC3B, and TFEB genes in vitro, significantly sensitized cells to radiotherapy and temozolomide (U87: P < 0.01 and < 0.05, respectively; T98: P < 0.01 and < 0.01, respectively). Silencing of the LC3A gene sensitized mouse xenografts to radiation. Conclusions:Autophagy in cancer cells may be a key factor of radio-resistance and chemo-resistance in glioblastoma cells. Blocking autophagy may improve the efficacy of radiochemotherapy for glioblastoma patients.