Claudin-4-targeting of diphtheria toxin fragment A using a C-terminal fragment of Clostridium perfringens enterotoxin
Claudin-4-targeting of diphtheria toxin fragment A using a C-terminal fragment of Clostridium perfringens enterotoxin
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DOI：
10.1016/j.ejpb.2010.03.003
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发表时间：
2010-06-01
影响因子：
4.9
通讯作者：
Yagi, Kiyohito
中科院分区：
文献类型：
--
作者：
Kakutani, Hideki;Kondoh, Masuo;Yagi, Kiyohito
Claudin (CL)-4是一种紧密连接蛋白，在一些人类肿瘤中过度表达，包括卵巢癌、乳腺癌、胰腺癌和前列腺癌。靶向治疗CL-4是一种新的肿瘤治疗策略。我们之前发现产气荚膜梭菌肠毒素（C-CPE）的c端片段与CL-4结合。本研究通过将C-CPE与白喉毒素片段a （DTA）融合，制备了一种新的cl -4靶向分子（DTA-C-CPE）。虽然DTA对表达cl -4的L细胞没有毒性，但即使在20 μ g/ml的浓度下，DTA- c - cpe对表达cl -4的L细胞也有毒性。DTA-C-CPE诱导的细胞毒性被C-CPE而不是牛血清白蛋白预处理的细胞减弱，这表明DTA-C-CPE可能通过其C-CPE结构域与表达cl -4的L细胞结合。为了评估DTA-C-CPE的特异性，我们检测了其在表达CL-1、-2、-4或-5的L细胞中的细胞毒性作用。我们发现DTA-C-CPE仅对表达cl -4的L细胞有毒性。因此，C-CPE可能是开发癌症靶向系统的有前途的配体。(C) 2010 Elsevier B.V.版权所有
Claudin (CL)-4, a tight junction protein, is overexpressed in some human neoplasias, including ovarian, breast, pancreatic and prostate cancers. The targeting of CL-4 is a novel strategy for tumor therapy. We previously found that the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) binds to CL-4. In the present study, we genetically prepared a novel CL-4-targeting molecule (DTA-C-CPE) by fusion of C-CPE and diphtheria toxin fragment A (DTA). Although DTA is not toxic to CL-4-expressing L cells, even at 20 mu g/ml, DTA-C-CPE is toxic to CL-4-expressing L cells at 1 mu g/ml. DTA-C-CPE-induced cytotoxicity was attenuated by pretreatment of the cells with C-CPE but not bovine serum albumin, indicating that DTA-C-CPE may bind to CL-4-expressing L cells through its C-CPE domain. To evaluate the specificity of DTA-C-CPE, we examined its cytotoxic effects in L cells that express CL-1, -2, -4 or -5. We found that DTA-C-CPE was toxic to only CL-4-expressing L cells. Thus, C-CPE may be a promising ligand for the development of cancer-targeting systems. (C) 2010 Elsevier B.V. All rights reserved.