Abstract
Prostaglandin E2 receptor EP4 is involved in inflammation and related tumorigenesis in the colorectum. This study aimed to investigate the chemopreventive ability of RQ-15986, a selective EP4 antagonist, in colitis-related colorectal tumorigenesis. Male Kyoto APC delta rats, which have APC mutations, were treated with azoxymethane and dextran sulfate sodium and subsequently administered RQ-15986 for eight weeks. At the end of the experiment, the development of colorectal tumor was significantly inhibited in the RQ-15986-treated group. The cell proliferation of the crypts and tumors in the colorectum was decreased following RQ-15986 treatment. RQ-15986 also suppressed the expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, interleukin-18, and monocyte chemotactic protein-1, in the colon mucosa. In addition, the expression levels of indoleamine 2,3-dioxygenase, which is involved in immune tolerance, were decreased in the colorectal epithelium and tumors of the RQ-15986-treated group. These findings indicate that RQ-15986 inhibits colitis-associated colorectal tumorigenesis by attenuating inflammation, suppressing cell proliferation, and modulating the expression of indoleamine 2,3-dioxygenase. Targeting prostaglandin E2/EP4 signaling might be a useful strategy for chemoprevention of inflammation-related colorectal cancer.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenomatous Polyposis Coli Protein / genetics*
-
Animals
-
Azoxymethane / toxicity
-
Benzamides / pharmacology
-
Carcinogenesis / genetics
-
Cell Proliferation / drug effects
-
Chemokine CCL2 / genetics
-
Colonic Neoplasms / chemically induced
-
Colonic Neoplasms / drug therapy*
-
Colonic Neoplasms / genetics
-
Colonic Neoplasms / pathology
-
Dextran Sulfate / toxicity
-
Dinoprostone / antagonists & inhibitors
-
Dinoprostone / genetics*
-
Gene Expression Regulation, Neoplastic / drug effects
-
Humans
-
Inflammation / chemically induced
-
Inflammation / drug therapy*
-
Inflammation / genetics
-
Inflammation / pathology
-
Interleukin-18 / genetics
-
Interleukin-6 / genetics
-
Mutation / genetics
-
Rats
-
Receptors, Prostaglandin E, EP4 Subtype / genetics*
-
Signal Transduction / drug effects
-
Tumor Necrosis Factor-alpha / genetics
Substances
-
(S)-4-(1-(5-chloro-2-(4-fluorophenyoxy) benzamido)ethyl) benzoic acid
-
APC protein, human
-
Adenomatous Polyposis Coli Protein
-
Benzamides
-
Ccl2 protein, rat
-
Chemokine CCL2
-
Interleukin-18
-
Interleukin-6
-
Receptors, Prostaglandin E, EP4 Subtype
-
Tumor Necrosis Factor-alpha
-
Dextran Sulfate
-
Dinoprostone
-
Azoxymethane
Grants and funding
Japan Society for the Promotion of Science (JSPS) provided support for this study in the form of KAKENHI grants awarded to MK (25860529, 17K15936, 20K08284). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.