Lin Hwai-Jeng, Liu Hsin-Ho, Lin Chia-Der, Kao Min-Chuan, Chen Yu-An, Chiang-Ni Chuan, Jiang Zhi-Pei, Huang Mei-Zi, Lin Chun-Jung, Lo U-Ging, Lin Li-Chiung, Lai Cheng-Kuo, Lin Ho, Hsieh Jer-Tsong, Chiu Cheng-Hsun, Lai Chih-Ho
Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical UniversityTaipei, Taiwan.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang-Ho HospitalNew Taipei, Taiwan.
Front Cell Infect Microbiol. 2017 Jun 8;7:223. doi: 10.3389/fcimb.2017.00223. eCollection 2017.
Cytolethal distending toxin (CDT) produced by contains three subunits: CdtA, CdtB, and CdtC. Among these three toxin subunits, CdtB is the toxic moiety of CDT with DNase I activity, resulting in DNA double-strand breaks (DSB) and, consequently, cell cycle arrest at the G2/M stage and apoptosis. Radiation therapy is an effective modality for the treatment of localized prostate cancer (PCa). However, patients often develop radioresistance. Owing to its particular biochemical properties, we previously employed CdtB as a therapeutic agent for sensitizing radioresistant PCa cells to ionizing radiation (IR). In this study, we further demonstrated that CDT suppresses the IR-induced autophagy pathway in PCa cells by attenuating c-Myc expression and therefore sensitizes PCa cells to radiation. We further showed that CDT prevents the formation of autophagosomes via decreased high-mobility group box 1 (HMGB1) expression and the inhibition of acidic vesicular organelle (AVO) formation, which are associated with enhanced radiosensitivity in PCa cells. The results of this study reveal the detailed mechanism of CDT for the treatment of radioresistant PCa.
由[具体产生菌]产生的细胞致死性膨胀毒素（CDT）包含三个亚基：CdtA、CdtB和CdtC。在这三个毒素亚基中，CdtB是具有DNA酶I活性的CDT毒性部分，会导致DNA双链断裂（DSB），进而导致细胞周期在G2/M期停滞并引发细胞凋亡。放射治疗是治疗局限性前列腺癌（PCa）的有效方式。然而，患者常常会产生放射抗性。由于其特殊的生化特性，我们之前将CdtB用作治疗剂，以使放射抗性PCa细胞对电离辐射（IR）敏感。在本研究中，我们进一步证明，CDT通过减弱c-Myc表达来抑制PCa细胞中IR诱导的自噬途径，从而使PCa细胞对辐射敏感。我们还进一步表明，CDT通过降低高迁移率族蛋白B1（HMGB1）表达以及抑制酸性囊泡细胞器（AVO）形成来阻止自噬体的形成，而这与PCa细胞放射敏感性增强相关。本研究结果揭示了CDT治疗放射抗性PCa的详细机制。
