RT Journal Article
SR Electronic
T1 C Terminus of <em>Clostridium perfringens</em> Enterotoxin Downregulates CLDN4 and Sensitizes Ovarian Cancer Cells to Taxol and Carboplatin
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 1065
OP 1074
DO 10.1158/1078-0432.CCR-10-1644
VO 17
IS 5
A1 Gao, Zhijian
A1 Xu, Xiaoyin
A1 McClane, Bruce
A1 Zeng, Qing
A1 Litkouhi, Babak
A1 Welch, William R.
A1 Berkowitz, Ross S.
A1 Mok, Samuel C.
A1 Garner, Elizabeth I.O.
YR 2011
UL http://clincancerres.aacrjournals.org/content/17/5/1065.abstract
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