C Terminus of Clostridium perfringens Enterotoxin Downregulates CLDN4 and Sensitizes Ovarian Cancer Cells to Taxol and Carboplatin
C Terminus of Clostridium perfringens Enterotoxin Downregulates CLDN4 and Sensitizes Ovarian Cancer Cells to Taxol and Carboplatin
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DOI：
10.1158/1078-0432.ccr-10-1644
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发表时间：
2011-03-01
影响因子：
11.5
通讯作者：
Garner, Elizabeth I. O.
中科院分区：
文献类型：
--
作者：
Gao, Zhijian;Xu, Xiaoyin;Garner, Elizabeth I. O.
目的：我们先前已经表明，CLDN 4（编码claudin-4），一种细胞紧密连接（TJ）蛋白，在人上皮性卵巢癌（EOC）中高度表达，但在正常卵巢中检测不到。CLDN 4已被鉴定为产气荚膜梭菌肠毒素（C-CPE）C末端的特异性受体，C-CPE是一种可以破坏TJ屏障功能并增强细胞吸收的无毒分子。本研究的目的是确定潜在的临床应用C-CPE和其对CLDN 4的表达在EOC.Experimental Design的影响：使用三维培养模型和单层培养的EOC细胞，我们研究了C-CPE对CLDN 4的表达的影响，通过定量实时PCR，免疫荧光和Western blot。在EOC培养和异种移植小鼠中观察到C-CPE对临床相关化疗（泰素和卡铂）的协同作用。此外，我们确定通过寡核苷酸芯片分析，转录谱改变失调的C-CPE treatment.Results的后果：C-CPE治疗降低蛋白质表达和重新定位CLDN 4从细胞-细胞接触区域的细胞质。特别地，C-CPE使EOC细胞对低剂量的化疗剂施用敏感，并且以无毒的方式显著抑制肿瘤生长。此外，我们提供了全基因组的分子证据表明，C-CPE治疗参与的泛素-蛋白酶体途径的刺激和细胞代谢的抑制在EOC cells.Conclusions：除了C-CPE可以增强紫杉醇或卡铂的有效性，并显着抑制EOC细胞生长的CLDN 4依赖的方式，这表明C-CPE可能有希望的治疗潜力EOC。临床癌症研究; 17（5）; 1065-74。（C）2010年AACR。
Purpose: We have previously shown that CLDN4 (encoding claudin-4), a cell tight junction (TJ) protein, is highly expressed in human epithelial ovarian carcinomas (EOC) but undetectable in normal ovaries. CLDN4 has been identified as a specific receptor for C terminus of Clostridium perfringens enterotoxin (C-CPE), a nontoxic molecule that may disrupt TJ barrier function and enhance cellular absorption. The purpose of this study was to determine the potential clinical applications of C-CPE and its effects on CLDN4 expression in EOC.Experimental Design: Using a 3-dimensional culture model and monolayer culture of EOC cells, we examined the effects of C-CPE on CLDN4 expression by quantitative real-time PCR, immunofluorescence, and Western blot. The synergistic effect of C-CPE to clinically relevant chemotherapies (Taxol and Carboplatin) was observed in EOC culture and xenograft mice. Furthermore, we determined through oligonucleotide microarray analysis that the transcript profile alterations dysregulated as a consequence of C-CPE treatment.Results: C-CPE treatment decreased protein expression and relocated CLDN4 from cell-cell contact regions to the cytoplasm. Particularly, C-CPE sensitized EOC cells to chemotherapeutic administration at low dosages and significantly inhibited tumor growth in a nontoxic manner. Furthermore, we provided genome-wide molecular evidence that C-CPE treatment is involved in the stimulation of the ubiquitin-proteasome pathway and the inhibition of cell metabolism in EOC cells.Conclusions: The addition of C-CPE can enhance the effectiveness of Taxol or Carboplatin and significantly inhibited EOC cell growth in a CLDN4-dependent manner, suggesting that C-CPE may have promising therapeutic potential for EOC. Clin Cancer Res; 17(5); 1065-74. (C)2010 AACR.