Prostaglandin E receptor subtype EP(1) deficiency inhibits colon cancer development.
Prostaglandin E(2) exerts its biological activity through binding to its membrane receptors, E-prostanoid (EP) receptors. Our previous finding that lack of EP(1) receptor inhibits the early stages of colon carcinogenesis led us to investigate whether EP(1) receptor deficiency reduces colon cancer development induced by azoxymethane (AOM) using EP(1) receptor knockout mice. At 6 weeks of age 33 homozygous EP(1)-deficient (EP(1)(-/-)) mice and 28 wild-type (EP(1)(+/+)) mice were given i.p. AOM (10 mg/kg body wt) once a week for 6 weeks. At 56 weeks of age all animals were killed and intestinal tumors were examined. The results clearly indicated that lack of EP(1) receptor significantly reduced colon cancer incidence (27 versus 57%, P < 0.05) and multiplicity (0.30 versus 0.76, P < 0.05) as well as tumor volume (12.2 versus 75.6 mm(3), P < 0.05). In EP(1)(-/-) mice, silver stained nucleolar organization region protein count as cell proliferation marker was significantly reduced (1.35 versus 2.17, P < 0.001) and apoptosis was significantly increased (0.685 versus 0.077, P < 0.001) in colon tumors induced by AOM compared with those in EP(1)(+/+) mice. We confirmed that EP(1) receptor mRNA was overexpressed in colon cancers of EP(1)(+/+) mice using reverse transcription-polymerase chain reaction. These results provide strong evidence that the EP(1) receptor is of major importance for colon cancer development and it could be a new target for a mechanism-based chemoprevention strategy against colon cancer development.
Kawamori
Toshihiko
T
Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. kawamori@musc.edu
Kitamura
Tomohiro
T
Watanabe
Kouji
K
Uchiya
Naoaki
N
Maruyama
Takayuki
T
Narumiya
Shuh
S
Sugimura
Takashi
T
Wakabayashi
Keiji
K
D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001397:Azoxymethane / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype
C545636:Ptger1 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; C061570:protein kinase N; D011493:Protein Kinase C; D001397:Azoxymethane