Deletion of cyclooxygenase-2 inhibits K-ras–induced lung carcinogenesis

The purpose of this study was to identify the role COX-2 plays in K-ras–induced lung carcinogenesis. We crossed COX-2–homozygous knockout mice with K-ras(LA1) (G12D) expressing mice to obtain COX-2–deficient mice with K-ras expression (K-ras/COX-2(−/−) mice) and COX-2 wild type mice with K-ras expression (K-ras mice). At 3.5 months of age, the K-ras/COX-2(−/−) mice had significantly fewer lung adenocarcinomas and substantially smaller tumors than K-ras mice. K-ras/COX-2(−/−) mice also had significantly fewer bronchioalveolar hyperplasias than K-ras mice. Compared with lung tumors from K-Ras mice, the levels of prostaglandin E(2) (PGE(2)) were significantly lower, whereas levels of the PGE(2) metabolite 13,14-dihydro-15-keto-PGE(2) were significantly higher, in lung tumors from K-ras/COX-2(−/−) mice. In addition, K-ras/COX-2(−/−) mice had strikingly lower rates of tumor cell proliferation and expressed less MEK and p-Erk1/2 protein than K-ras mice did. In line with this, knocking down COX-2 in mutant K-ras non-small cell lung cancer A549 cells reduced colony formation, PGE(2) synthesis and ERK phosphorylation compared to that of vector control cells. Taken together, these findings suggest that COX-2 deletion contributes to the repression of K-ras–induced lung tumorigenesis by reducing tumor cell proliferation, decreasing the production of PGE(2), and increasing the production of 13,14-dihydro-15-keto-PGE(2), possibly via the MAPK pathway. Thus, COX-2 is likely important in lung tumorigenesis, and COX-2 and its product, PGE(2), are potential targets for lung cancer prevention.