Endoplasmic Reticulum Stress Mediates Radiation-Induced Autophagy via PERK-eIF2α in Caspase-3/7 Deficient Cells

Since apoptosis defects limit efficacy of anti-cancer agents, autophagy has been proposed as a novel strategy for radiotherapy enhancement. We previously showed that caspase-3/7 inhibition induces autophagy and promotes radiosensitivity in vitro and in vivo. Therefore, we further investigated the mechanism by which radiation triggers autophagy in caspase-3/7 deficient cells, and found the involvement of Endoplasmic Reticulum (ER) stress. The ER activates a survival pathway, the unfolded protein response, which involves ER-localized transmembrane proteins PERK, IRE1, and ATF6. In this study, we found that PERK is essential for radiation-induced autophagy and radiosensitivity in caspase-3/7 double-knockout cells. Irradiation of these cells increased expression of phosphorylated-elf2α. Similar results were seen following administration of tunicamycin (TM), a well known ER stressor. Importantly, we found that the administration of TM with radiation in MCF-7 breast cancer cells, which are lacking functional caspase-3 and relatively resistant to many anti-cancer agents, enhances radiation sensitivity. Our findings reveal ER stress as a novel potential mechanism of radiation-induced autophagy in caspase-3/7 deficient cells and as a potential strategy to maximize efficiency of radiation therapy in breast cancer.