Oral administration of E-type prostanoid (EP) 1 receptor antagonist suppresses carcinogenesis and development of prostate cancer via upregulation of apoptosis in an animal model

Masahito Masato,Akihiro Asai,Yuta Mukae,Kyohei Araki,Yuichiro Nakamura,Tsuyoshi Matsuda,Kensuke Mitsunari,Kojiro Ohba,Yasuyoshi Miyata,Tomohiro Matsuo,Hidenori Ito,Hideki Sakai,Hiroki Kurata,Junki Harada

doi:10.1038/s41598-021-99694-y

Abstract

Prostaglandin E2 plays an important role in carcinogenesis and malignant potential of prostate cancer (PC) cells by binding to its specific receptors, E-type prostanoid (EP) receptors. However, anti-carcinogenic effects of the EP receptor antagonist are unclear. In this study, we used a mouse model of PC. The mice were provided standard feed (control) or feed containing the EP1 receptor antagonist and were sacrificed at 10, 15, 30, and 52 weeks of age. Apoptosis was evaluated by immunohistochemical analysis using a cleaved caspase-3 assay. The incidence of cancer in the experimental group was significantly lower than that in the control group at 15, 30, and 52 weeks of age. The percentage of poorly differentiated PC cells was significantly lower in the experimental group than in the control group at 30 and 52 weeks of age. The percentage of apoptotic cells in the experimental group was significantly higher than that in the control group at 15, 30, and 52 weeks of age. These findings indicate that feeding with the addition of EP1 receptor antagonist delayed PC progression via the upregulation of apoptosis. We suggest that the EP1 receptor antagonist may be a novel chemopreventive agent for PC.

Highlights

Prostaglandin E2 plays an important role in carcinogenesis and malignant potential of prostate cancer (PC) cells by binding to its specific receptors, E-type prostanoid (EP) receptors
We confirmed that expression of the EP1 receptor was detected in all PC tissues of both the experimental and control groups
At 15 weeks of age, cancer cells were relatively rare in the experimental group (Fig. 2A); carcinogenic changes in the prostate glands were found in the control group (Fig. 2B)

Summary

Introduction

Prostaglandin E2 plays an important role in carcinogenesis and malignant potential of prostate cancer (PC) cells by binding to its specific receptors, E-type prostanoid (EP) receptors. The percentage of apoptotic cells in the experimental group was significantly higher than that in the control group at 15, 30, and 52 weeks of age These findings indicate that feeding with the addition of EP1 receptor antagonist delayed PC progression via the upregulation of apoptosis. COX-2 inhibitors, including nonsteroid anti-inflammatory drugs, are reported to act as tumor suppressors via regulation of PGE2 in many types of cancers[12,13], COX-2 inhibitors do not always inhibit the pathological activities of PGE2. Many investigators have suggested that the PGE2/EP receptor axes in PC play important pathological roles in malignant potential and tumor g rowth[16,17,18,19,20]. The influence of the EP1 receptor antagonist on apoptosis in PC cells in the same mouse tissues was assessed

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