Intestinal tumor suppression in ApcMin/+ mice by prostaglandin D2 receptor PTGDR

Cancer Medicine

Brigette L. Tippin⁶  Alan M. Kwong⁶  Michael J. Inadomi⁶  Oliver J. Lee⁶  Jae Man Park⁶  Alicia M. Materi⁶  Virgilio S. Buslon⁴  Amy M. Lin⁶  Lili C. Kudo¹  Stanislav L. Karsten¹  Samuel W. French⁴  Shuh Narumiya⁵  Yoshihiro Urade²  Eduardo Salido³ 

[1] NeuroInDx, Inc., Signal Hill, California;Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan;CIBERER, Hospital Universitario Canarias, La Laguna, Spain;Department of Pathology, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, California;Department of Pharmacology, Faculty of Medicine, University of Kyoto, Kyoto, Japan;Department of Pediatrics, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, California

关键词: Adenomatous polyposis coli;    gastrointestinal neoplasms;    PPAR gamma;    prostaglandin D2 receptor;    prostaglandin D2 synthases;   

DOI  :  10.1002/cam4.251

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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