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Carcinogenesis Advance Access published online on November 25, 2004
Carcinogenesis, doi:10.1093/carcin/bgh322
© 2004 by Oxford University Press
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Received May 26, 2004
Revised October 11, 2004
Accepted October 19, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Prostaglandin E receptor subtype EP1 deficiency inhibits colon cancer development

Toshihiko Kawamori 1*, Tomohiro Kitamura 1, Kouji Watanabe 1, Naoaki Uchiya 1, Takayuki Maruyama 2, Shuh Narumiya 3, Takashi Sugimura 1, and Keiji Wakabayashi 1

1 Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045 Japan
2 Minase Research Institute, Ono Pharmaceutical Co. Ltd., Osaka 618-8585 Japan
3 Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto 606-8315 Japan

* To whom correspondence should be addressed.
Toshihiko Kawamori, E-mail: Kawamori{at}musc.edu


  Abstract

Prostaglandin E2 (PGE2) exerts its biological activity through binding to its membrane receptors, E-prostanoid (EP) receptors1~4. Our previous finding that lack of EP1 receptor inhibits the early stages of colon carcinogenesis led us to investigate whether EP1 receptor deficiency reduces colon cancer development induced by azoxymethane (AOM) using EP1 receptor knockout mice. At 6 weeks of age, 33 EP1 deficiency homozygous (EP1-/-) mice and 28 wild type (EP1+/+) mice were given intraperitoneal injection of AOM (10 mg/kg body weight) once a week for 6 weeks. At 56 weeks of age, all animals were sacrificed and intestinal tumors were examined. The results clearly indicated that lack of EP1 receptor significantly reduced colon cancer incidence (27 vs. 57%, P<0.05) and multiplicity (0.30 vs. 0.76, P<0.05) as well as tumor volume (12.2 vs. 75.6 mm3, P<0.05). In EP1-/- mice, silver-stained nucleolar organization region protein (AgNOR) count as cell proliferation marker was significantly reduced (1.35 vs. 2.17, P<0.001) and apoptosis was significantly increased (0.685 vs. 0.077, P<0.001) in colon tumors induced by AOM compared to those in EP1+/+ mice. We confirmed that EP1 receptor mRNA was overexpressed in colon cancers of EP1+/+ mice using reverse transcription-polymerase chain reaction (RT-PCR). These results provide strong evidence that EP1 receptor is of major importance for colon cancer development and EP1 receptor is a new target for mechanism-based chemoprevention strategy against colon cancer development.


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