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

Yohei Shirakami,Noritaka Ozawa,Masahito Shimizu,Takayuki Nakanishi,Takahiro Kochi,Takayasu Ideta,Masaya Kubota,Takuji Tanaka,Hiroyasu Sakai,Takashi Ibuka,Emiko Mizoguchi

doi:10.1371/journal.pone.0251942

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.

Highlights

Colorectal cancer (CRC) is one of the most serious health concerns owing to its high morbidity and mortality
COX-2/prostaglandin E2 (PGE2)/EP4 signaling plays a critical role in inflammation and tumorigenesis of the colorectum [6,7,8]
Clinical trials have revealed the effectiveness of these agents in the prevention of CRC; these studies failed eventually due to severe adverse events such as cardiovascular toxicity [25]

Summary

Introduction

Colorectal cancer (CRC) is one of the most serious health concerns owing to its high morbidity and mortality. Because the prevalence of CRC has increased gradually worldwide [1], there is a critical need to develop more effective strategies to prevent and treat this malignancy. Chronic inflammation is widely accepted as a major risk factor for CRC. Patients with inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease, are at high risk of CRC [2]. Several inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, are involved in the development of colitis-associated cancer [3]. It has been reported that attenuation of inflammation is effective for preventing colitis-related CRC [4]

Objectives

Methods

Results

Conclusion