15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors.
Pharmacologic 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.
Yan
Min
M
Department of Medicine and Pathology, Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.
Myung
Seung-Jae
SJ
Fink
Stephen P
SP
Lawrence
Earl
E
Lutterbaugh
James
J
Yang
Peiying
P
Zhou
Xiaohua
X
Liu
Danielle
D
Rerko
Ronald M
RM
Willis
Joseph
J
Dawson
Dawn
D
Tai
Hsin-Hsiung
HH
Barnholtz-Sloan
Jill S
JS
Newman
Robert A
RA
Bertagnolli
Monica M
MM
Markowitz
Sanford D
SD
D000236:Adenoma / Q000517:prevention & control*; D000818:Animals; D000068579:Celecoxib; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000517:prevention & control*; D003113:Colonoscopy; D004335:Drug and Narcotic Control; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011720:Pyrazoles / Q000378:metabolism / Q000627:therapeutic use*; D013449:Sulfonamides / Q000378:metabolism / Q000627:therapeutic use*
D011720:Pyrazoles; D013449:Sulfonamides; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D000068579:Celecoxib