Published in:
01-03-2008 | Basic Science
Cyclooxygenase-2 Inhibition Prevents Migration of Colorectal Cancer Cells to Extracellular Matrix by Down-Regulation of Matrix Metalloproteinase-2 Expression
Published in: Diseases of the Colon & Rectum | Issue 3/2008
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Purpose
Matrix metalloproteinases-2 hydrolyses gelatins and collagens. It has many biologic functions, including cancer cells invasion. Overexpression of cyclooxygenase-2 is known to be involved in colorectal carcinogenesis, although the mechanism is unclear. Up-regulation of matrix metalloproteinases-2 expression may be one of the mechanisms, which explains how cyclooxygenase-2 expression promotes migration of colorectal cancer cells to extracellular matrix.
Methods
Colorectal cancer cell lines HT29, CaCO2, and Colo205 were used. By using flow cytometry, their cyclooxygenase-2 expression was determined. These cell lines were modulated with NS398, a selective cyclooxygenase-2-inhibitor, and prostaglandin-E2. Western blot and enzyme-linked inmmunosorbent assay were used to determine these cells’ matrix metalloproteinases-2 expression. These cell lines’ ability to migrate into extracellular matrix was determined by Matrigel® (Millipore, Watford, UK) Invasion Chamber.
Results
HT29 expressed more cyclooxygenase-2 than CaCO2. Cyclooxygenase-2 was not detected in Colo205. Matrix metalloproteinases-2 expression is highest in HT29 and least in Colo205. Cyclooxygenase-2 inhibition by NS398 showed decreased matrix metalloproteinases-2 expression in HT29 and CaCO2, but not Colo205, reversible with prostaglandin-E2. Prostaglandin-E2 was shown to up-regulate matrix metalloproteinases-2 expression in all cell lines. Matrigel® Invasion Chamber demonstrated that many more HT29 cells migrate across the membrane than CaCO2 and Colo205, and cyclooxygenase-2 inhibition reduced cellular migration in the cyclooxygenase-2–positive cell lines. Prostaglandin-E2 promoted migration in all cell lines.
Conclusions
There is a positive relationship between cyclooxygenase-2 and matrix metalloproteinases-2 expression. The latter is modulated by prostaglandin-E2 in all cell lines and NS398 in cyclooxygenase-2–positive cells. Such modulation has a knock-on effect to the cells’ ability to invade into extracellular matrix. Cyclooxygenase-2 and matrix metalloproteinases-2 expression are potential therapeutic targets into prevention of colorectal cancer metastasis.