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Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice

Nature Medicine volume 7, pages 1048–1051 (2001)Cite this article

Abstract

Arachidonic acid is metabolized to prostaglandin H2 (PGH2) by cyclooxygenase (COX). COX-2, the inducible COX isozyme, has a key role in intestinal polyposis1,2. Among the metabolites of PGH2, PGE2 is implicated in tumorigenesis because its level is markedly elevated in tissues of intestinal adenoma and colon cancer3. Here we show that homozygous deletion of the gene encoding a cell-surface receptor of PGE2, EP2, causes decreases in number and size of intestinal polyps in ApcΔ716 mice (a mouse model for human familial adenomatous polyposis). This effect is similar to that of COX-2 gene disruption. We also show that COX-2 expression is boosted by PGE2 through the EP2 receptor via a positive feedback loop. Homozygous gene knockout for other PGE2 receptors, EP1 or EP3, did not affect intestinal polyp formation in ApcΔ716 mice. We conclude that EP2 is the major receptor mediating the PGE2 signal generated by COX-2 upregulation in intestinal polyposis, and that increased cellular cAMP stimulates expression of more COX-2 and vascular endothelial growth factor in the polyp stroma.

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Figure 1: COX-2 and EP receptors in ApcΔ716 polyps.
Figure 2: Effects of EP gene disruptions on ApcΔ716 polyps.
Figure 3: Effects of COX-2 or EP gene disruption on gene expression.

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Acknowledgements

We thank K. Hioki and N. Shimozawa for breeding mice; and H. Seno, S. Iwasaki and S. Hagiwara for assistance. This study was supported in part by the Joint Research Fund between the University of Tokyo and Banyu Pharmaceutical, grants from the Ministry of Education, Science, Sports and Culture (MESSC; Cancer Research) and the Organization for Pharmaceutical Safety and Research (OPSR), Japan.

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Authors and Affiliations

  1. Laboratory of Biomedical Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan

    Masahiro Sonoshita, Kazuaki Takaku, Nobuya Sasaki & Makoto M. Taketo

  2. Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Masahiro Sonoshita, Kazuaki Takaku, Shuh Narumiya, Masanobu Oshima & Makoto M. Taketo

  3. Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    Yukihiko Sugimoto

  4. Department of Pharmacology, Asahikawa Medical College, Asahikawa, Japan

    Fumitaka Ushikubi

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  1. Masahiro Sonoshita
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Correspondence to Makoto M. Taketo.

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Sonoshita, M., Takaku, K., Sasaki, N. et al. Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice. Nat Med 7, 1048–1051 (2001). https://doi.org/10.1038/nm0901-1048

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