15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors.
Fink, Stephen P
Rerko, Ronald M
Barnholtz-Sloan, Jill S
Newman, Robert A
Bertagnolli, Monica M
Markowitz, Sanford D
AffiliationDepartment of Medicine and Pathology, Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.
Local subject classificationCOLORECTAL CANCER
Drug and Narcotic Control
MetadataShow full item record
Citation15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors. 2009, 106 (23):9409-13 Proc. Natl. Acad. Sci. U.S.A.
JournalProceedings of the National Academy of Sciences of the United States of America
AbstractPharmacologic inhibitors of the prostaglandin-synthesizing COX-2 oncogene prevent the development of premalignant human colon adenomas. However, resistance to treatment is common. In this study, we show that the adenoma prevention activity of the COX-2 inhibitor celecoxib requires the concomitant presence of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) tumor suppressor gene, and that loss of 15-PGDH expression imparts resistance to celecoxib's anti-tumor effects. We first demonstrate that the adenoma-preventive activity of celecoxib is abrogated in mice genetically lacking 15-PGDH. In FVB mice, celecoxib prevents 85% of azoxymethane-induced tumors >1 mm in size, but is essentially inactive in preventing tumor induction in 15-PGDH-null animals. Indeed, celecoxib treated 15-PGDH null animals develop more tumors than do celecoxib naive WT mice. In parallel with the loss of tumor prevention activity, celecoxib-mediated suppression of colonic PGE(2) levels is also markedly attenuated in 15-PGDH-null versus WT mice. Finally, as predicted by the murine models, humans with low colonic 15-PGDH levels also exhibit celecoxib resistance. Specifically, in a colon adenoma prevention trial, in all cases tested, individuals who developed new adenomas while receiving celecoxib treatment were also found as having low colonic 15-PGDH levels.
CollectionsJournal articles & published research
- Sulindac reversal of 15-PGDH-mediated resistance to colon tumor chemoprevention with NSAIDs.
- Authors: Fink SP, Dawson DM, Zhang Y, Kresak A, Lawrence EG, Yang P, Chen Y, Barnholtz-Sloan JS, Willis JE, Kopelovich L, Markowitz SD
- Issue date: 2015 Feb
- 15-Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis.
- Authors: Myung SJ, Rerko RM, Yan M, Platzer P, Guda K, Dotson A, Lawrence E, Dannenberg AJ, Lovgren AK, Luo G, Pretlow TP, Newman RA, Willis J, Dawson D, Markowitz SD
- Issue date: 2006 Aug 8
- 15-Hydroxyprostaglandin dehydrogenase, a COX-2 oncogene antagonist, is a TGF-beta-induced suppressor of human gastrointestinal cancers.
- Authors: Yan M, Rerko RM, Platzer P, Dawson D, Willis J, Tong M, Lawrence E, Lutterbaugh J, Lu S, Willson JK, Luo G, Hensold J, Tai HH, Wilson K, Markowitz SD
- Issue date: 2004 Dec 14
- Celecoxib enhances the efficacy of 15-hydroxyprostaglandin dehydrogenase gene therapy in treating murine breast cancer.
- Authors: Zhang B, Ma X, Li Z, Gao X, Wang F, Liu L, Shen G, Sang Y, Li M, Li Y, Zhao J, Wei Y
- Issue date: 2013 May
- Regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) by non-steroidal anti-inflammatory drugs (NSAIDs).
- Authors: Tai HH, Chi X, Tong M
- Issue date: 2011 Nov