A SELECTIVE CYCLOOXYGENASE-2 INHIBITOR SUPPRESSES THE GROWTH OF H-RAS-TRANSFORMED RAT INTESTINAL EPITHELIAL-CELLS

Background & Aims: Constitutive expression of cyclooxygenase 2 (COX-2) has been found in 85% of colorectal cancers. Ras mutations are found in 50% of colorectal adenocarcinomas. The aim of this study was to det ermine the role of COX-2 in ras-induced transformation in rat intestin al epithelial (RIE) cells. Methods: Cell growth was determined by cell counts. The expression of COX-2 was examined by Northern and Western analyses. For tumorigenicity assays, cells were inoculated into dorsal subcutaneous tissue of athymic nude mice. DNA-fragmentation assays we re performed to detect apoptosis. Results: The expression of COX-2 was increased in RIE-Ras cells at both messenger RNA (9-fold) and protein (12-fold) levels. Prostaglandin I-2 levels were elevated 2.15-fold in RIE-Ras cells. Serum deprivation further increased COX-2 expression 3 .8-fold in RIE-Ras cells. Treatment with a selective COX-2 antagonist (SC58125) inhibited the growth of RIE-Ras cells through inhibition of cell proliferation and by induction of apoptosis. SC-58125 treatment r educed the colony formation in Matrigel by 83.0%. Intraperitoneal admi nistration of SC-58125 suppressed RIE-Ras tumor growth in nude mice by 60.3% in 4 weeks. SC-58125 treatment also induced apoptosis in RIE-Ra s cells as indicated by increased DNA fragmentation. Conclusions: Over expression of COX-2 may contribute to tumorigenicity of ras-transforme d intestinal epithelial cells. Selective inhibition of COX-2 activity inhibits growth of ras-transformed intestinal epithelial cells and ind uces apoptosis.