CHOP And JNK Mediate Radiation-induced Autophagy And Apoptosis Via Er Stress In Breast Cancer Cells

Endoplasmic reticulum(ER) stress generated by various physiological and pathological conditions may induce an accumulation of misfolded proteins in its lumen and activates the unfolded protein response(UPR) to cope with protein misfolding. However, severe or prolonged ER Stress results in apoptosis. Radiation- induced ER Stress elicits autophagy and apoptosis in cancer cells, in which C/EBP homologous protein(C HOP) and c JUN NH2-terminal kinase(JNK) may play crucial roles. However, accurate mechanisms governing the regulation of autophagy and apoptosis through CHOP and JNK after radiation and how the balance of these activities determines the cellular radiosensitivity remain largely unclear.In this study, breast cancer cells(MD-MB-231 and MCF-7) were irradiated by X-rays, and then examined by western blot analysis, q RT-PCR, flow cytometric analysis and clonogenicity assay. CHOP and JNK were silenced by si RNA and pharmacological inhibitor respectively to decipher their roles. We found that X-ray radiation induced ER Stress, UPR and high expression of CHOP and JNK; moreover, autophagy and apoptosis occurred in sequential order when breast cancer MDA-MB-231 and MCF-7 cells were exposed to X-rays. The treatment of CHOP gene knockdown with RNA interfering inhibited autophagy of MDA-MB-231 cells, while having an impact on apoptosis and subsequently increasing the radio-resistance of MCF-7 cells. However, the treatment with JNK inhibitor decreased the autophagic level but promoted cell apoptosis, thereby leading to a radio-sensitization in both cell lines. O ur results reveal that CHOP mediated autophagy and apoptosis induced by X-rays in cell context. Importantly, the uniformity of the JNK function suggests that JNK might be a better potential target to maximize the efficacy of radiation therapy against breast cancers.