Unfolded protein response (UPR) is comprised of complex and conserved stress pathways that function as a short-term adaptive mechanism to reduce levels of unfolded or misfolded proteins and maintain homeostasis in the endoplasmic reticulum (ER). UPR can be triggered by prolonged or persistent ER stress under many physiological or pathological conditions, including radiation exposure. Radiation-induced ER stress elicits autophagy and apoptosis in cancer cells, where C/EBP homologous protein (CHOP) and c-Jun NH2-terminal kinase (JNK) may play crucial roles. However, the specific mechanisms that regulate autophagy and apoptosis through CHOP and JNK after radiation exposure and how the balance of these activities determines the cellular radiosensitivity remain largely unclear. In this study, we found that exposure to X-ray radiation induced ER stress, UPR and high expression of CHOP and JNK. Furthermore, autophagy and apoptosis occurred in sequential order when breast cancer MDA-MB-231 and MCF-7 cells were exposed to X-ray radiation. CHOP gene knockdown with RNA interference inhibited autophagy and enhanced radiosensitivity in MDA-MB-231 cells, while impacting apoptosis and subsequently increasing radioresistance in MCF-7 cells. However, treatment with JNK inhibitor decreased autophagy while promoting apoptosis, thereby leading to radiosensitivity in both cell lines. Our results indicate that CHOP mediates radiation-induced autophagy and apoptosis in a cellular environment. Importantly, the functional consistency of regulating apoptosis and autophagy in these two irradiated breast cancer cell lines suggests that JNK may be more useful as a potential target for maximizing the efficacy of radiation therapy for breast cancers.
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1 May 2016
Research Article|
May 02 2016
Different Roles of CHOP and JNK in Mediating Radiation-Induced Autophagy and Apoptosis in Breast Cancer Cells
Feifei Li
;
Feifei Li
aInstitute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;
bKey Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;
cKey Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and
dUniversity of Chinese Academy of Sciences, Beijing 100049, China
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Xiaogang Zheng
;
Xiaogang Zheng
aInstitute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;
bKey Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;
cKey Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and
dUniversity of Chinese Academy of Sciences, Beijing 100049, China
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Yan Liu
;
Yan Liu
aInstitute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;
bKey Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;
cKey Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and
dUniversity of Chinese Academy of Sciences, Beijing 100049, China
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Ping Li
;
Ping Li
aInstitute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;
bKey Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;
cKey Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and
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Xiongxiong Liu
;
Xiongxiong Liu
aInstitute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;
bKey Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;
cKey Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and
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Fei Ye
;
Fei Ye
aInstitute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;
bKey Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;
cKey Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and
dUniversity of Chinese Academy of Sciences, Beijing 100049, China
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Ting Zhao
;
Ting Zhao
aInstitute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;
bKey Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;
cKey Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and
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Qingfeng Wu
;
Qingfeng Wu
aInstitute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;
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Xiaodong Jin
;
Xiaodong Jin
1
aInstitute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;
bKey Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;
cKey Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and
1Address for correspondence: Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou 730000, Gansu Province, China; email: liqiang@impcas.ac.cn, jinxd@impcas.ac.cn.
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Qiang Li
Qiang Li
1
aInstitute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;
bKey Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;
cKey Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and
1Address for correspondence: Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou 730000, Gansu Province, China; email: liqiang@impcas.ac.cn, jinxd@impcas.ac.cn.
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Radiat Res (2016) 185 (5): 539–548.
Article history
Received:
November 29 2015
Accepted:
February 22 2016
Citation
Feifei Li, Xiaogang Zheng, Yan Liu, Ping Li, Xiongxiong Liu, Fei Ye, Ting Zhao, Qingfeng Wu, Xiaodong Jin, Qiang Li; Different Roles of CHOP and JNK in Mediating Radiation-Induced Autophagy and Apoptosis in Breast Cancer Cells. Radiat Res 1 May 2016; 185 (5): 539–548. doi: https://doi.org/10.1667/RR14344.1
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