Inhibition of endoplasmic reticulum stress-induced autophagy promotes the killing effect of X-rays on sarcoma in mice.

Endoplasmic reticulum (ER) stress is a conserved cellular process for cells to clear unfolded or misfolded proteins and maintain cell homeostasis under stress conditions. Autophagy may act as a pro-survival strategy to cope with multiple stress conditions in tumor progression and distant metastasis. Although many studies have demonstrated that there is a close correlation between radiation-induced ER stress and autophagy, the molecular mechanisms currently remain unclear. In the present study, we performed an in vivo study concerning the effect of autophagy induced by ER stress on the radiosensitivity of mouse sarcoma using X-rays. Our results documented that X-rays could induce ER stress in sarcoma and then autophagy was activated by unfolded protein response (UPR) through the IRE1-JNK-pBcl2-Beclin1 signaling axis. The induction of autophagy caused a decline in cell apoptosis while inhibiting the autophagy resulted in increased apoptosis and inhibition of tumor progression. Combined treatment of X-ray exposure and chloroquine increased ER stress-related apoptosis and enhanced the radiosensitivity of mouse sarcoma that was not sensitive to X-ray irradiation alone. Thus, our study indicates that inhibition of ER stress-induced autophagy might be a novel strategy to improve the efficacy of radiotherapy against radioresistant sarcoma.