PT  - JOURNAL ARTICLE
AU  - Gao, Zhijian
AU  - Xu, Xiaoyin
AU  - McClane, Bruce
AU  - Zeng, Qing
AU  - Litkouhi, Babak
AU  - Welch, William R.
AU  - Berkowitz, Ross S.
AU  - Mok, Samuel C.
AU  - Garner, Elizabeth I.O.
TI  - C Terminus of <em>Clostridium perfringens</em> Enterotoxin Downregulates CLDN4 and Sensitizes Ovarian Cancer Cells to Taxol and Carboplatin
AID  - 10.1158/1078-0432.CCR-10-1644
DP  - 2011 Mar 01
TA  - Clinical Cancer Research
PG  - 1065--1074
VI  - 17
IP  - 5
4099  - http://clincancerres.aacrjournals.org/content/17/5/1065.short
4100  - http://clincancerres.aacrjournals.org/content/17/5/1065.full
SO  - Clin Cancer Res2011 Mar 01; 17
AB  - 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. ©2010 AACR. This article is featured in Highlights of This Issue, p. 947