Zheng Xiaogang, Jin Xiaodong, Li Feifei, Liu Xiongxiong, Liu Yan, Ye Fei, Li Ping, Zhao Ting, Li Qiang
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.
Med Oncol. 2017 Feb;34(2):25. doi: 10.1007/s12032-017-0883-8. Epub 2017 Jan 9.
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.
在癌症放射治疗中，高能碳离子（CI）相较于传统辐射如X射线或γ射线具有显著优势。在某些情况下，高传能线密度（LET）的CI可在肿瘤细胞中诱导内质网（ER）应激和自噬。对于暴露于高LET辐射的肿瘤中ER应激与自噬之间的分子联系以及这两条途径如何影响肿瘤治疗效果，目前仍知之甚少。在本研究中，我们研究了高LET CI辐射后由ER应激诱导的自噬和凋亡对S180细胞体外和体内放射敏感性的影响。在体外实验中，X射线也用作对照辐射。我们的结果表明，CI辐射与特殊的自噬抑制剂氯喹（CQ）联合使用，对S180细胞和异种移植肿瘤产生了更显著的增殖抑制作用。CI辐射与CQ联合处理可通过IRE1/JNK/Beclin-1轴阻断自噬，并在体外和体内通过IRE1途径而非PERK激活C/EBP同源蛋白（CHOP）来增强凋亡细胞死亡。因此，我们的研究表明，抑制自噬可能是CI放射治疗中一种有前景的治疗策略，可通过加重ER应激相关的凋亡来实现。
