title: The resistance to the tumor suppressive effects of COX inhibitors and COX-2 gene disruption in TRAMP mice is associated with the loss of COX expression in prostate tissue.
abstract: Over-expression of cyclooxygenase-2 (COX-2) and prostaglandin E(2) has been demonstrated to play a significant role in the tumorigenesis of colon, lung, breast, bladder and skin. However, inconsistent and controversial reports on the expression and activity of COX-2 in prostate cancer raised the question of whether COX-2 plays a pivotal role in prostate carcinogenesis. To address this question, we examined the effects of COX-2 inhibition on prostate tumorigenesis in the transgenic adenocarcinoma mouse prostate (TRAMP) model. Three-week-old TRAMP mice were fed control, celecoxib- or indomethacin-supplemented diets for 27 weeks. A TRAMP/COX-2 knockout mouse model was also generated to determine the effects of the loss of the COX-2 gene on prostate tumorigenesis in TRAMP mice. These studies demonstrated that neither non-steroidal anti-inflammatory drugs (NSAIDs) nor genetic disruption of COX-2 was inhibitory in terms of tumor and metastases incidence, lobe weight or types of pathological lesions. A careful analysis of wild-type and TRAMP tissues was undertaken for the expression of cyclooxygenase-1 (COX-1) and COX-2 using immunoblotting, quantitative real time polymerase chain reaction (qRT-PCR) and immunohistochemistry approaches in TRAMP dorsal prostate tissue from 10- and 16-week-old, as well as tumor from 30-week-old mice. We found that the expression of COX-1 and COX-2 dramatically decreased during TRAMP carcinogenesis. Using the probasin promoter, a COX-2 over-expressing mouse model was also generated but failed to show any pathology in any of the prostate lobes. Collectively, our results suggest that COX-2 may not play a tumorigenic role during prostate carcinogenesis in the TRAMP model.
authors.affiliation: Department of Human Nutrition and Molecular Carcinogenesis and Chemoprevention Program, The Ohio State University Comprehensive Cancer Center, The Ohio State University, 325 Campbell Hall, 1787 Neil Avenue, Columbus, OH 43210, USA.
authors.forename: Xingya
authors.initials: X
authors.lastname: Wang
authors.forename: Jennifer K L
authors.initials: JK
authors.lastname: Colby
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fischer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Newman
authors.forename: Russell D
authors.initials: RD
authors.lastname: Klein
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011467:Prostate / Q000201:enzymology*; D011471:Prostatic Neoplasms / Q000201:enzymology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D051546:Cyclooxygenase 2