title: Inhibiting autophagy with chloroquine enhances the anti-tumor effect of high-LET carbon ions via ER stress-related apoptosis.
abstract: Energetic carbon ions (CI) offer great advantages over conventional radiations such as X- or γ-rays in cancer radiotherapy. High linear energy transfer (LET) CI can induce both endoplasmic reticulum (ER) stress and autophagy in tumor cells under certain circumstances. The molecular connection between ER stress and autophagy in tumor exposed to high-LET radiation and how these two pathways influence the therapeutic effect against tumor remain poorly understood. In this work, we studied the impact of autophagy and apoptosis induced by ER stress following high-LET CI radiation on the radiosensitivity of S180 cells both in vitro and in vivo. In the in vitro experiment, X-rays were also used as a reference radiation. Our results documented that the combination of CI radiation with chloroquine (CQ), a special autophagy inhibitor, produced more pronounced proliferation suppression in S180 cells and xenograft tumors. Co-treatment with CI radiation and CQ could block autophagy through the IRE1/JNK/Beclin-1 axis and enhance apoptotic cell death via the activation of C/EBP homologous protein (CHOP) by the IRE1 pathway rather than PERK in vitro and in vivo. Thus, our study indicates that inhibiting autophagy might be a promising therapeutic strategy in CI radiotherapy via aggravating the ER stress-related apoptosis.
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, China.|Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China.|Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu Province, China.|University of Chinese Academy of Sciences, Beijing, 100049, China.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, China.|Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China.|Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu Province, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Jin
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, China.|Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China.|Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu Province, China.|University of Chinese Academy of Sciences, Beijing, 100049, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Li
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, China.|Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China.|Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu Province, China.
authors.forename: Xiongxiong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, China.|Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China.|Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu Province, China.|University of Chinese Academy of Sciences, Beijing, 100049, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, China.|Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China.|Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu Province, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, China.|Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China.|Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu Province, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, China.|Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China.|Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu Province, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, China. liqiang@impcas.ac.cn.|Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China. liqiang@impcas.ac.cn.|Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu Province, China. liqiang@impcas.ac.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001343:Autophagy / Q000187:drug effects / Q000528:radiation effects; D002244:Carbon; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002738:Chloroquine / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000528:radiation effects*; D005260:Female; D005434:Flow Cytometry; D063193:Heavy Ion Radiotherapy / Q000379:methods*; D020450:Heavy Ions; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011897:Random Allocation; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: C497250:Ddit3 protein, mouse; D008565:Membrane Proteins; D051742:Transcription Factor CHOP; D002244:Carbon; D002738:Chloroquine; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Apoptosis; Autophagy; CHOP; Chloroquine; ER stress; High-LET radiation