Abstract
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-rasLA1 (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 E2 (PGE2) were significantly lower, whereas levels of the PGE2 metabolite 13,14-dihydro-15-keto-PGE2 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, PGE2 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 PGE2, and increasing the production of 13,14-dihydro-15-keto-PGE2, possibly via the MAPK pathway. Thus, COX-2 is likely important in lung tumorigenesis, and COX-2 and its product, PGE2, are potential targets for lung cancer prevention.
Original language | English (US) |
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Pages (from-to) | 38816-38826 |
Number of pages | 11 |
Journal | Oncotarget |
Volume | 6 |
Issue number | 36 |
DOIs | |
State | Published - 2015 |
Keywords
- COX-2
- K-ras oncogene
- Lung adenocarcinoma
- MAP kinase
- Mouse
ASJC Scopus subject areas
- Oncology
MD Anderson CCSG core facilities
- Research Animal Support Facility
- Small Animal Imaging Facility