Claudin-4-targeted therapy using Clostridium perfringens enterotoxin for prostate cancer
Claudin-4-targeted therapy using Clostridium perfringens enterotoxin for prostate cancer
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DOI：
10.1002/pros.21436
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发表时间：
2012-03-01
期刊：
影响因子：
2.8
通讯作者：
Sawada, Norimasa
中科院分区：
文献类型：
--
作者：
Maeda, Toshihiro;Murata, Masaki;Sawada, Norimasa
背景：产气荚膜梭菌肠毒素(CPE)通过与前列腺癌中过度表达的紧密连接蛋白Cldn3(Cldn3)和Cldn4结合来触发上皮细胞的溶解。方法我们研究了Cldn3和Cldn4在人前列腺癌组织、人前列腺癌细胞系(22Rv1、DU145和PC3)和正常前列腺上皮细胞(PrECs)中的表达水平和亚细胞定位。用比色法检测CPE对这些细胞的细胞毒作用。我们研究了使用RNA干扰技术抑制Cldn3和/或Cldn4表达是否影响CPE介导的细胞毒作用。结果：Cldn4和Cldn3在人前列腺癌原代组织22Rv1、DU145和PC3中均有表达。癌前病变组织中有Cldn4蛋白表达。Cldn4在癌细胞株中分布于整个细胞膜，而在癌前病变中定位于紧密连接。CPE介导的细胞毒作用在PC3细胞中大量检测到，而在PREC中几乎检测不到。Cldn4的表达减少，但Cldn3没有，导致PC3和22Rv1的细胞毒性显著降低。在PC3移植瘤周围注射CPE可显著抑制肿瘤生长。结论CPE介导的细胞毒作用在人前列腺癌细胞系中可观察到，但在正常人前内皮细胞中几乎检测不到。其细胞毒作用不仅与Cldn4蛋白的表达水平有关，还与其在细胞内的定位有关。这些结果表明，使用CPE的Cldn4靶向治疗可能是前列腺癌的一种新疗法。前列腺癌72：351-360,2012。(C)2011年威利期刊公司。
BACKGROUND Clostridium perfringens enterotoxin (CPE) triggers lysis of epithelial cells through binding to tight-junction proteins claudin-3 (Cldn3) and Cldn4, which are over-expressed in prostate cancer. We investigated the potential of Cldn-targeted therapy using CPE.METHODS. We investigated the expression levels and subcellular localization of Cldn3 and Cldn4 in primary human prostate cancer tissues, human prostate cancer cell lines (22Rv1, DU145, and PC3) and normal human prostate epithelial cells (PrECs). Cytotoxic effects of CPE on these cells were examined by colorimetric assay. We studied whether knockdown of Cldn3 and/or Cldn4 expression using RNA interference influenced CPE-mediated cytotoxicity. The therapeutic effect of CPE was evaluated in PC3 xenografts in athymic mice.RESULTS. Cldn4 and Cldn3 were expressed in primary human prostate cancer tissues, 22Rv1, DU145, and PC3. Cldn4 protein was expressed in PrEC. Cldn4 was distributed along whole cell membranes of the cancer cell lines, whereas it was localized at tight junctions in PrEC. CPE-mediated cytotoxicity was greatly detected in PC3, but was hardly detectable in PrEC. Reduced expression of Cldn4, but not Cldn3, led to remarkable decreases of cytotoxicity in both PC3 and 22Rv1. The injection of CPE around PC3 xenografts significantly suppressed tumor growth.CONCLUSION. CPE-mediated cytotoxicity was observed in human prostate cancer cell lines, but barely detected in normal human PrECs. The cytotoxic effect depended not only on the expression level of Cldn4 protein but also on its subcellular localization. These results suggest that Cldn4-targeted therapy using CPE may be a new treatment for prostate cancer. Prostate 72: 351-360, 2012. (C) 2011 Wiley Periodicals, Inc.