Cyclooxygenase-2 alters transforming growth factor-beta 1 response during intestinal tumorigenesis

Background: Recent investigation suggests that cyclooxygenase plays an impo rtant role it colorectal carcinogenesis. Transforming growth factor-beta 1 (TGF-beta 1) Is one of the most potent stimulators gf cyclooxygenase-2 expr ession. A key step in intestinal tumorigenesis involves alteration of the n ormal cellular response to TGF-beta 1. We have synthesized that overexpress ion of cyclooxygenase-2 alters intestinal epithelial response to TGF-beta 1 . Methods: RIE-1 cells were stably transfected with rat cyclooxygenase-2 comp lementary DNA in either the sense (RIE-S) or antisense (RIE-AS) orientation . Tumor cell invasion was assessed with a modified Boyden collagen type I I nvasion assay in the presence of TGF-beta 1, antibody to urokinase plasmino gen activator (uPA), or the selective cyclooxygenase-2 inhibitor SC-58125. Expression of uPA, uPA receptor and plasminogen activator inhibitor-1 were determined by Western blot and enzyme-linked immunosorbent bent assay. Results: RIE-I and RIE-AS did not invade although RIE-S cells were minimall y invasive at baseline. TGF-beta 1 had no effect on RTE-1 or RIE-AS invasio n; however; TGF-beta 1 significantly upregulated RIE-S cell Invasion. All 3 RIE cell lines produce minimal uPA under basal conditions. TGF-beta 1 upre gulated uPA production only in the RIE-S cells. Both antibody to uPA and SC -58125 reversed TGF-beta-mediated RIE-S cell invasion. SC-58125 inhibited T GF-beta-mediated RIE-S uPA production. Conclusions: These results demonstrate that overexpression of cyclooxygenas e-2 alters intestinal epithelial I response to TGF-beta 1, which may be a m echanism by which cyclooxygenase-2 promotes colon carcinogenesis.