Claudin-6: a novel receptor for CPE-mediated cytotoxicity in ovarian cancer.
Claudin-6: a novel receptor for CPE-mediated cytotoxicity in ovarian cancer.
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DOI：
10.1038/oncsis.2012.32
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发表时间：
2012-11-12
期刊：
影响因子：
6.2
通讯作者：
Morin, P. J.
中科院分区：
文献类型：
--
作者：
Lal-Nag, M.;Battis, M.;Santin, A. D.;Morin, P. J.
紧密连接蛋白是一种紧密连接蛋白，负责维持上皮细胞结构和细胞极性的完整性。紧密连接蛋白-3和紧密连接蛋白-4在几种癌症中过表达，并且已经显示出作为产气荚膜梭菌肠毒素（CPE）的受体，CPE是一种引起快速细胞溶解的毒素。CPE已证明可以有效治疗小鼠模型中的几种不同癌症，前提是这些癌症表达密蛋白-3或密蛋白-4。在这里，我们表明，claudin-3/4的表达是不是一个绝对的CPE行动的要求，并通过过表达和敲低实验，我们确定claudin-6作为一种新的功能性受体CPE。事实上，UCI-101，一种对CPE高度敏感的卵巢癌细胞系，不表达claudin-3/4，并且在这些细胞中敲低claudin-6降低CPE敏感性。此外，两种不同的卵巢细胞系，耐CPE的影响，可以通过claudin-6过表达敏感。结合测定显示CPE确实可以结合细胞中的密蛋白-6，并且这种结合与CPE细胞毒性相关。多细胞肿瘤球体实验表明，claudin-6也可以是三维培养物中CPE的靶标。我们的数据确立了claudin-6作为CPE的新型受体，并为表达claudin-6的卵巢癌和其他癌症引入了新型靶向治疗的可能性。
Claudins are integral tight junction proteins that are responsible for maintaining the integrity of epithelial cell architecture and cell polarity. Claudin-3 and -4 are overexpressed in several cancers and have been shown to act as receptors for the Clostridium perfringens enterotoxin (CPE), a toxin that causes rapid cell lysis. CPE has demonstrated effectiveness in treating several different cancers in mouse models, provided that these cancers express claudin-3 or claudin-4. Here, we show that claudin-3/4 expression is not an absolute requirement for CPE action and, through overexpression and knockdown experiments, we identify claudin-6 as a novel functional receptor for CPE. Indeed, UCI-101, an ovarian cancer cell line highly sensitive to CPE, does not express claudin-3/4 and knockdown of claudin-6 in these cells decreases CPE sensitivity. Moreover, two different ovarian cell lines that are resistant to the effects of CPE can be made sensitive through claudin-6 overexpression. Binding assays show that CPE can indeed bind claudin-6 in cells and that this binding is associated with CPE cytotoxicity. Multicellular tumor spheroids experiments demonstrate that claudin-6 can also be a target of CPE in three-dimensional cultures. Our data establish claudin-6 as a novel receptor for CPE and introduces the possibility of a novel targeted therapeutic for ovarian and other cancers that express claudin-6.
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DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1097/pas.0b013e31822cfa7e
发表时间：
2012-01
期刊：
The American journal of surgical pathology
影响因子：
--
作者：
Sullivan LM;Yankovich T;Le P;Martinez D;Santi M;Biegel JA;Pawel BR;Judkins AR
通讯作者：
Judkins AR
影响因子：
4.7
作者：
Bignotti, Eliana;Tassi, Renata A.;Santin, Alessandro D.
通讯作者：
Santin, Alessandro D.
影响因子：
29.4
作者：
Michl, P;Buchholz, M;Gress, TM
通讯作者：
Gress, TM
影响因子：
6.4
作者：
Santin, AD;Zhan, FH;Pecorelli, S
通讯作者：
Pecorelli, S