Intestinal tumor suppression in ApcMin/+ mice by prostaglandin D2 receptor PTGDR. (12th April 2014)

• Record Type: Journal Article
• Authors: Tippin, Brigette L.; Kwong, Alan M.; Inadomi, Michael J.; Lee, Oliver J.; Park, Jae Man; Materi, Alicia M.; Buslon, Virgilio S.; Lin, Amy M.; Kudo, Lili C.; Karsten, Stanislav L.; French, Samuel W.; Narumiya, Shuh; Urade, Yoshihiro; Salido, Eduardo; Lin, Henry J.
• Is Part Of: Cancer medicine. Volume 3:Number 4(2014:Aug.)
• Page Start: 1041
• Page End: 1051
• Publication Date: 2014-04-12
• Subjects: 616.994005
• DOI: 10.1002/cam4.251
• Languages: English
• ISSNs: 2045-7634

Abstract

<abstract abstract-type="main" id="cam4251-abs-0001"> <title>Abstract</title> <p>Our earlier work showed that knockout of hematopoietic prostaglandin D synthase (HPGDS, an enzyme that produces prostaglandin D<sub>2</sub>) caused more adenomas in <italic>Apc</italic><sup>Min/+</sup> mice. Conversely, highly expressed transgenic HPGDS allowed fewer tumors. Prostaglandin D<sub>2</sub> (PGD<sub>2</sub>) binds to the prostaglandin D<sub>2</sub> receptor known as PTGDR (or DP1). PGD<sub>2</sub> metabolites bind to peroxisome proliferator‐activated receptor <italic>γ</italic> (PPARG). We hypothesized that <italic>Ptgdr</italic> or <italic>Pparg</italic> knockouts may raise numbers of tumors, if these receptors take part in tumor suppression by PGD<sub>2</sub>. To assess, we produced <italic>Apc</italic><sup>Min/+</sup> mice with and without <italic>Ptgdr</italic> knockouts (147 mice). In separate experiments, we produced <italic>Apc</italic><sup>Min/+</sup> mice expressing transgenic lipocalin‐type prostaglandin D synthase (PTGDS), with and without heterozygous <italic>Pparg</italic> knockouts (104 mice). Homozygous <italic>Ptgdr</italic> knockouts raised total numbers of tumors by 30–40% at 6 and 14 weeks. Colon tumors were not affected. Heterozygous <italic>Pparg</italic> knockouts alone did not affect tumor numbers in <italic>Apc</italic><sup>Min/+</sup> mice. As mentioned above, our <italic>Pparg</italic> knockout assessment also included mice with highly expressed <italic>PTGDS</italic> transgenes. <italic>Apc</italic><sup>Min/+</sup> 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 <italic>Pparg</italic> knockouts appeared to blunt the tumor‐suppressing effect of transgenic PTGDS. However, tumor suppression by PGD<sub>2</sub> 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 PGD<sub>2</sub> signals acting through PTGDR in suppression of intestinal tumors.</p> </abstract>