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

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.

• Authors: Yong Pan, Yan Jiang, Lin Tan, Murali K Ravoori, Mihai Gagea, Vikas Kundra, Susan M Fischer, Peiying Yang
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 36 Pg. 38816-26 (Nov 17 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26452035 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• KRAS protein, human
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• PTGS2 protein, human
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)
• Dinoprostone

Topics

• Adenocarcinoma (enzymology, genetics, pathology)
• Adenocarcinoma of Lung
• Animals
• Carcinogenesis (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cyclooxygenase 2 (deficiency, genetics, metabolism)
• Dinoprostone (biosynthesis)
• Female
• Gene Knockout Techniques
• Genes, ras
• Genetic Predisposition to Disease
• Humans
• Lung Neoplasms (enzymology, genetics, pathology)
• MAP Kinase Signaling System
• Male
• Mice
• Mice, Knockout
• Proto-Oncogene Proteins p21(ras) (antagonists & inhibitors, genetics)
• Signal Transduction