Cytolethal Distending Toxin Enhances Radiosensitivity in Prostate Cancer Cells by Regulating Autophagy.
Cytolethal Distending Toxin Enhances Radiosensitivity in Prostate Cancer Cells by Regulating Autophagy.
复制标题
DOI：
10.3389/fcimb.2017.00223
复制
发表时间：
2017
影响因子：
5.7
通讯作者：
Lai CH
中科院分区：
文献类型：
--
作者：
Lin HJ;Liu HH;Lin CD;Kao MC;Chen YA;Chiang-Ni C;Jiang ZP;Huang MZ;Lin CJ;Lo UG;Lin LC;Lai CK;Lin H;Hsieh JT;Chiu CH;Lai CH
空肠弯曲杆菌产生的细胞致死膨胀毒素 (CDT) 包含三个亚基：CdtA、CdtB 和 CdtC。在这三个毒素亚基中，CdtB 是 CDT 的毒性部分，具有 DNase I 活性，导致 DNA 双链断裂 (DSB)，从而导致细胞周期停滞在 G2/M 阶段并导致细胞凋亡。放射治疗是治疗局限性前列腺癌（PCa）的有效方法。然而，患者常常会产生放射抗药性。由于其特殊的生化特性，我们之前使用 CdtB 作为治疗剂，使抗辐射 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。我们进一步表明，CDT 通过减少高迁移率族蛋白 1 (HMGB1) 表达和抑制酸性囊泡细胞器 (AVO) 形成来防止自噬体的形成，这与 PCa 细胞的放射敏感性增强有关。本研究的结果揭示了CDT治疗抗放射PCa的详细机制。
Cytolethal distending toxin (CDT) produced by Campylobacter jejuni 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.