Inhibitory effects of a selective prostaglandin E2 receptor antagonist RQ-15986 on inflammation-related colon tumorigenesis in APC-mutant rats.

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.

• Authors: Yohei Shirakami, Takayuki Nakanishi, Noritaka Ozawa, Takayasu Ideta, Takahiro Kochi, Masaya Kubota, Hiroyasu Sakai, Takashi Ibuka, Takuji Tanaka, Masahito Shimizu
• Journal: PloS one (PLoS One) Vol. 16 Issue 5 Pg. e0251942 ( 2021) ISSN: 1932-6203 [Electronic] United States
• PMID: 34003864 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (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

Topics

• Adenomatous Polyposis Coli Protein (genetics)
• Animals
• Azoxymethane (toxicity)
• Benzamides (pharmacology)
• Carcinogenesis (genetics)
• Cell Proliferation (drug effects)
• Chemokine CCL2 (genetics)
• Colonic Neoplasms (chemically induced, drug therapy, genetics, pathology)
• Dextran Sulfate (toxicity)
• Dinoprostone (antagonists & inhibitors, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Inflammation (chemically induced, drug therapy, genetics, 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)