title: 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.affiliation: Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Murali K
authors.initials: MK
authors.lastname: Ravoori
authors.affiliation: Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.affiliation: Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Kundra
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fischer
authors.affiliation: Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D055786:Gene Knockout Techniques; D011905:Genes, ras; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction
chemical_list: C117307:KRAS protein, human; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D015232:Dinoprostone
keywords: COX-2; K-ras oncogene; MAP kinase; lung adenocarcinoma; mouse