Hematopoietic prostaglandin D synthase suppresses intestinal adenomas in ApcMin/+ mice.
Aspirin and other nonsteroidal anti-inflammatory drugs prevent some cases of colon cancer by inhibiting prostaglandin (PG) synthesis. PGE(2) promotes colon neoplasia, as shown by knockout mouse studies on enzymes and receptors in the PG cascade. A few experiments 20 to 30 years ago suggested that PGD(2) may suppress tumors, but a role for biosynthetic enzymes for PGD(2) in tumor development has not been studied. We report here that disruption of the gene for hematopoietic PGD synthase in Apc(Min/+) mice led to approximately 50% more intestinal adenomas compared with controls. Tumor size was not affected. By immunohistochemistry, we detected hematopoietic PGD synthase mainly in macrophages and monocytes of the gut mucosa. The mean number of tumors did not increase with knockout of the gene for the lipocalin type of the enzyme, which is not produced in the intestine. On the other hand, Apc(Min/+) mice with transgenic human hematopoietic PGD synthase tended to have 80% fewer intestinal adenomas. The transgene produced high mRNA levels (375-fold over endogenous). There was a suggestion of higher urinary excretion of 11beta-PGF(2alpha) and a lower excretion of a PGE(2) metabolite in transgenic mice, but differences (30-40%) were not statistically significant. The results support an interpretation that hematopoietic PGD synthase controls an inhibitory effect on intestinal tumors. Further studies will be needed to prove possible mechanisms, such as routing of PG production away from protumorigenic PGE(2) or inhibition of the nuclear factor-kappaB cascade by PGD(2) metabolites.
Park
Jae Man
JM
Division of Medical Genetics, Department of Pediatrics and Department of Pathology, Los Angeles Biomedical Research Institute, Harbor-University of California-Los Angeles Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA.
Kanaoka
Yoshihide
Y
Eguchi
Naomi
N
Aritake
Kosuke
K
Grujic
Sava
S
Materi
Alicia M
AM
Buslon
Virgilio S
VS
Tippin
Brigette L
BL
Kwong
Alan M
AM
Salido
Eduardo
E
French
Samuel W
SW
Urade
Yoshihiro
Y
Lin
Henry J
HJ
D011125:Adenomatous Polyposis Coli / Q000201:enzymology* / Q000235:genetics / Q000652:urine; D000818:Animals; D015237:Dinoprost / Q000652:urine; D005260:Female; D006413:Hematopoietic System / Q000201:enzymology*; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D054834:Lipocalins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015230:Prostaglandin D2 / Q000096:biosynthesis; D011453:Prostaglandins / Q000652:urine
D054834:Lipocalins; D011453:Prostaglandins; C060526:7-hydroxy-5,11-dioxotetranorprostane-1,16-dioic acid; D015237:Dinoprost; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2