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Cyclooxygenase‐2 and RhoA Signaling Disrupts Cell‐Cell Adhesion by the Regulation of the Transcriptional Repressor, ZEB‐1
Author(s) -
Bean Ronald R.,
Jakobi Rolf,
Marlin Jerry,
Chang YuWen E.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.882.2
Subject(s) - rhoa , adherens junction , cadherin , gene silencing , microbiology and biotechnology , cell adhesion , repressor , signal transduction , chemistry , cell , biology , cancer research , transcription factor , gene , biochemistry
Cyclooxygenase 2 (COX‐2) plays a critical role in colon cancer and loss of the adhesion molecule E‐cadherin is one of the hallmarks that indicate a tumor cell has become invasive. The aim for this study is to investigate if the transcription repressor ZEB1 is a crucial component linking COX‐2 and RhoA/ROCK signaling to down‐regulation of E‐cadherin. In the cells lines that expressed COX‐2 , activity of RhoA was elevated, and formation adherens junctions were disrupted, which was concomitant with down‐regulation of E‐cadherin. In contrast, inhibition of COX‐2, inactivation of RhoA by expressing dominant negative RhoA or inhibition of ROCK, restored E‐cadherin levels in the same COX‐2 expressing cells. Quantitative real‐time RT‐PCR showed that E‐cadherin was down‐regulated at transcriptional level in cells expressing COX‐2. Furthermore, both protein and mRNA levels of ZEB1 were highly elevated in cells expressing COX‐2. We also found that expression of constitutively active RhoA resulted in increased ZEB1 and decreased E‐cadherin expression, which were prevented when ROCK was inhibited. Importantly, silencing ZEB1 expression in cells expressing COX‐2 markedly increased E‐cadherin mRNA and protein levels. Thus, our results showed for the first time that the RhoA/ROCK pathway mediates COX‐2 signaling to increase ZEB1 expression, which is required to modulate E‐cadherin and formation of adherens junctions.