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Regulation of tumor cell invasion and metastasis by COX‐2 and RhoA
Author(s) -
Chang YuWen Edith,
Sheets Damon M.,
Jakobi Rolf
Publication year - 2006
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.20.5.a984
Subject(s) - rhoa , adherens junction , cancer research , microbiology and biotechnology , catenin , cell , cadherin , biology , chemistry , signal transduction , wnt signaling pathway , biochemistry
Cyclooxygenase 2 (COX‐2) is a key enzyme in prostaglandin biosynthesis and represents an important target for treatment and prevention of colorectal cancer. Colon epithelial cells are joined by adherens junctions (AJs) in which the core components include E‐cadherin, β‐catenin and α‐catenin. Down regulation of E‐cadherin or dysregulation of small GTPase RhoA results in loss of AJs and consequently, leads to loss of epithelial cell shape and stimulation of invasion. In this study, we examined the molecular mechanisms by which COX‐2 regulates formation of AJs. We detected elevated levels of RhoA protein and activity in HCA‐7 colon carcinoma cells that constitutively express COX‐2. Treatment of HCA‐7 cells with the COX‐2 inhibitor NS398 significantly reduced the levels of RhoA activity. Little α‐catenin was detected at AJs of HCA‐7 cells, suggesting formation of AJs is disrupted. In contrast, NS398 treatment stimulated the formation of AJs. Levels of E‐cadherin were significantly low in HCA‐7 cells but were stimulated when COX‐2 or RhoA activity was inhibited. In addition, silencing of COX‐2 or RhoA expression by RNA interference increased the E‐cadherin levels in HCA‐7 cells. Our data showed that disruption of AJs in HCA‐7 colon carcinoma cells is the result of constitutive expression of COX‐2 and high levels of RhoA activity. Furthermore, we showed that constitutive expression of COX‐2 stimulates the activity of RhoA, suggesting RhoA mediates COX‐2 signaling to disrupt AJs. Disruption of adherens junctions promotes tumor cell invasion and metastasis. Therefore, COX‐2 and RhoA play important roles in promotion of invasion and metastasis in colorectal cancer.