A selective cyclooxygenase 2 inhibitor suppresses the growth of H-ras-transformed rat intestinal epithelial cells.

Sheng GG, Shao J, Sheng H, Hooton EB, Isakson PC, Morrow JD, Coffey RJ, DuBois RN, Beauchamp RD
Gastroenterology. 1997 113 (6): 1883-91

PMID: 9394727 · DOI:10.1016/s0016-5085(97)70007-6

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 determine the role of COX-2 in ras-induced transformation in rat intestinal 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 were 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 I2 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 reduced the colony formation in Matrigel by 83.0%. Intraperitoneal administration 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-Ras cells as indicated by increased DNA fragmentation.

CONCLUSIONS - Overexpression of COX-2 may contribute to tumorigenicity of ras-transformed intestinal epithelial cells. Selective inhibition of COX-2 activity inhibits growth of ras-transformed intestinal epithelial cells and induces apoptosis.

MeSH Terms (21)

Animals Apoptosis Carcinogenicity Tests Cell Division Cell Transformation, Neoplastic Collagen Cyclooxygenase 2 DNA Drug Combinations Enzyme Inhibitors Genes, ras Intestinal Mucosa Intestinal Neoplasms Isoenzymes Laminin Mice Mice, Nude Prostaglandin-Endoperoxide Synthases Proteoglycans Pyrazoles Rats

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