Carcinogenesis Advance Access published online on October 17, 2007
Carcinogenesis, doi:10.1093/carcin/bgm226
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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
1 The Ohio State University, Department of Human Nutrition and the Ohio State University Comprehensive Cancer Center, Molecular Carcinogenesis and Chemoprevention Program, 325 Campbell Hall, 1787 Neil Avenue, Columbus, OH 43210
2 The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, P.O. Box 389, Park Rd. 1C, Smithville, TX 78957
3 The University of Texas M.D. Anderson Cancer Center, Department of Experimental Therapeutics, 8000 El Rio, Houston, TX 77054
4 Correspondence should be addressed to Susan M. Fischer, The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, P.O. Box 389, Park Rd. 1C, Smithville, TX 78957; Phone: (512) 237-9482; E-mail: smfischer{at}mdanderson.org
Overexpression of cyclooxgenase-2 (COX-2) and prostaglandin E2 (PGE2) have been demonstrated to play a significant role in the tumorigenesis of colon, lung, breast, bladder, and skin cancer. 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 wk 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 prostate tissues was undertaken for the expression of COX-1 and COX-2 using immunoblotting, qRT-PCR and immunohistochemistry approaches in TRAMP dorsal prostate tissue from mice 10 and 16 wk old, as well as tumor from 30 wk old mice. We found that the expression of COX-1 and COX-2 dramatically decreased during TRAMP prostate carcinogenesis. Using the probasin promoter, a COX-2 overexpressing 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.
Key Words: COX-2 • NSAIDs • TRAMP • COX-2 knockout mice • prostate
Received July 5, 2007; revised September 13, 2007; accepted October 2, 2007.