CHOP and JNK mediate radiation-induced Apoptosis and Autophagy via unfolded protein response in Brea

• 作 者: Li Feifei Jin Xiaodong Li Qiang
• 机 构: Institute of Modern Physics,Chinese Academy of Sciences,Lanzhou 730000,China;Key Laboratory of Heavy
• 出 处: The 15th Asia-Oceania Congress of Medical Physics (AOCMP2015
• 发表日期: 2015年7期
• 关键词: Radiation ER Stress Apoptosis Autophagy CHOP JNK

　　Background and purpose: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.The molecular mechanism that UPR manipulates cellular survival and death is unclear.Here,we investigate the possible pathways of UPR and the roles of CHOP and JNK,as well the linkage among UPR,autophagy and apoptosis in the radiation response of breast cancer cells.Method:Breast cancer cells(MD-MB-231 and MCF-7)were irradiated by X-rays,and then examined by western blot analysis,qRT-PCR,flow cytometric analysis and clongenicity assay.CHOP and JNK were silenced by siRNA and pharmacological inhibitor respectively to decipher their roles.Results:We found that the expression of Bip and CHOP,as well the phosphorylated levels of JNK and eIf2α,were promoted by x-rays radiation,indicating the occurrence of ER stress and UPR in breast cancer cells MDA-MB-231 and MCF-7 after irradiation.Simultaneously,the levels of autophagy and apoptosis increased at the shorter time points(4,12h)and the longer time points(24,48h)after 2 Gy radiation,respectively.Intriguingly,inhibition CHOP using siRNA,which is a key molecule of PERK-eIF2a pathway,downregulated the autophagy level in MDA-MB-231 cells during the early stage and suppressed the apoptosis in MCF-7 cells.Pharmacological activated JNK inhibition by SP600125 pre-treatment,that is a key protein in IRE1a pathway,depressed the radiation-induced autophay formation significantly whereas the co-treatment had no effect on apoptosis in both cell lines.Conclusions:Our finding reveal that ER Stress as a novel potential mechanism of radiation-induced apoptosis and autophagy,moreover,CHOP and JNK can serve as potential targets to maximize efficiency of radiation therapy in breast cancer.