Prostaglandin endoperoxide synthase 2, also referred to as cyclooxygenase 2 (COX-2), is a key enzyme in the conversion of arachidonic acid to prostaglandins and other eicosanoids. Rat intestinal epithelial(RIE) cells were permanently transfected with a COX-2 expression vector oriented in the sense(RIE-S) or antisense (RIE-AS) direction. The RIE-S cells expressed elevated COX-2 protein levels and demonstrated increased adhesion to extracellular matrix (ECM) proteins. E-cadherin was undetectable in RIE-S cells, but was elevated in parental RIE (RIE-P) and RIE-AS cells. RIE-S cells were resistant to butyrate-induced apoptosis, had elevated BCL2 protein expression, and reduced transforming growth factor p2 receptor levels. The phenotypic changes involving both increased adhesion to ECM and inhibition of apoptosis were reversed by sulindac sulfide (a COX inhibitor). These studies demonstrate that overexpression of COX-2 leads to phenotypic changes in intestinal epithelial cells that could enhance their tumorigenic potential.