title: Intestinal tumor suppression in ApcMin/+ mice by prostaglandin D2 receptor PTGDR.
abstract: Our earlier work showed that knockout of hematopoietic prostaglandin D synthase (HPGDS, an enzyme that produces prostaglandin D2) caused more adenomas in Apc(Min/+) mice. Conversely, highly expressed transgenic HPGDS allowed fewer tumors. Prostaglandin D2 (PGD2) binds to the prostaglandin D2 receptor known as PTGDR (or DP1). PGD2 metabolites bind to peroxisome proliferator-activated receptor γ (PPARG). We hypothesized that Ptgdr or Pparg knockouts may raise numbers of tumors, if these receptors take part in tumor suppression by PGD2. To assess, we produced Apc(Min/+) mice with and without Ptgdr knockouts (147 mice). In separate experiments, we produced Apc(Min/+) mice expressing transgenic lipocalin-type prostaglandin D synthase (PTGDS), with and without heterozygous Pparg knockouts (104 mice). Homozygous Ptgdr knockouts raised total numbers of tumors by 30-40% at 6 and 14 weeks. Colon tumors were not affected. Heterozygous Pparg knockouts alone did not affect tumor numbers in Apc(Min/+) mice. As mentioned above, our Pparg knockout assessment also included mice with highly expressed PTGDS transgenes. Apc(Min/+) mice with transgenic PTGDS had fewer large adenomas (63% of control) and lower levels of v-myc avian myelocytomatosis viral oncogene homolog (MYC) mRNA in the colon. Heterozygous Pparg knockouts appeared to blunt the tumor-suppressing effect of transgenic PTGDS. However, tumor suppression by PGD2 was more clearly mediated by receptor PTGDR in our experiments. The suppression mechanism did not appear to involve changes in microvessel density or slower proliferation of tumor cells. The data support a role for PGD2 signals acting through PTGDR in suppression of intestinal tumors.
authors.affiliation: Department of Pediatrics, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, California.
authors.forename: Brigette L
authors.initials: BL
authors.lastname: Tippin
authors.forename: Alan M
authors.initials: AM
authors.lastname: Kwong
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Inadomi
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Lee
authors.forename: Jae Man
authors.initials: JM
authors.lastname: Park
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Materi
authors.forename: Virgilio S
authors.initials: VS
authors.lastname: Buslon
authors.forename: Amy M
authors.initials: AM
authors.lastname: Lin
authors.forename: Lili C
authors.initials: LC
authors.lastname: Kudo
authors.forename: Stanislav L
authors.initials: SL
authors.lastname: Karsten
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Eduardo
authors.initials: E
authors.lastname: Salido
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Lin
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D005260:Female; D015870:Gene Expression; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019746:Intramolecular Oxidoreductases; D007535:Isomerases / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics; D015230:Prostaglandin D2 / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D047495:PPAR gamma; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D025521:Tumor Suppressor Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; C545516:HPGDS protein, mouse; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor
keywords: Adenomatous polyposis coli; PPAR gamma; gastrointestinal neoplasms; prostaglandin D2 receptor; prostaglandin D2 synthases
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