COX-2-PGE2-EPs in gynecological cancers

Yao Ye,Udo Jeschke,Viktoria Von Schönfeldt,Xipeng Wang

doi:10.1007/s00404-020-05559-6

Abstract

PurposeNonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (COXibs) inhibit the progression of endometrial cancer, ovarian cancer and cervical cancer. However, concerning the adverse effects of NSAIDs and COXibs, it is still urgent and necessary to explore novel and specific anti-inflammation targets for potential chemoprevention. The signaling of cyclooxygenase 2-prostaglandin E2-prostaglandin E2 receptors (COX-2-PGE2-EPs) is the central inflammatory pathway involved in the gynecological carcinogenesis.MethodsLiterature searches were performed to the function of COX-2-PGE2-EPs in gynecological malignancies.ResultsThis review provides an overview of the current knowledge of COX-2-PGE2-EPs signaling in endometrial cancer, ovarian cancer and cervical cancer. Many studies demonstrated the upregulated expression of the whole signaling pathway in gynecological malignancies and some focused on the function of COX-2 and cAMP-linked EP2/EP4 and EP3 signaling pathway in gynecological cancer. By contrast, roles of EP1 and the exact pathological mechanisms have not been completely clarified. The studies concerning EP receptors in gynecological cancers highlight the potential advantage of combining COX enzyme inhibitors with EP receptor antagonists as therapeutic agents in gynecological cancers.ConclusionEPs represent promising anti-inflammation biomarkers for gynecological cancer and may be novel treatment targets in the near future.

Highlights

Abundant literature has demonstrated a strong correlation between chronic inflammation and cancer development since chronic inflammation contributes to the development of over 15% of malignancies worldwide [1]
Arachidonic acid is released from the membrane phospholipids by phospholipase A2 (PLA2) and metabolized by the enzyme of COX-1 and COX-2 into prostaglandin H2 (PGH2). PGH2 is converted by specific isomerases (PGDS, PGES, PGFS and PGIS) and TXA synthase to various prostaglandins (PGE2, PGD2, PGF2α, PGI2) and the thromboxane A2 (TxA2) [4] (Fig. 1)
This study demonstrated that HPV16 E5 upregulated the activity of PGE2-EP4-cAMP signaling pathways by inducing the binding of cyclic adenosine monophosphate response elementbinding protein (CREB) to a variant CRE site in the promoter of the human EP4 gene [83]

Summary

Introduction

Abundant literature has demonstrated a strong correlation between chronic inflammation and cancer development since chronic inflammation contributes to the development of over 15% of malignancies worldwide [1]. The co-expression of COX-2 and thymidine phosphorylase (TP) is related to poor 5-year disease-free and overall survival rates, suggesting that the combination of COX-2 and TP is a prognosticator for squamous cell carcinoma of the cervical cancer [79]. Sales et al reported that the syntheses of COX-2, PGE2, EP2, EP4 and cyclic adenosine monophosphate (cAMP) are up-regulated in cervical cancer tissue compared to that in the healthy cervix, suggesting that P GE2 may regulate neoplastic cell function via the EP2/EP4 receptors [75] Sales and his colleagues further in 2002 proved that P GE2 could induce the expression of COX-2, EP4 and cAMP in Hela cells which were transiently transfected with EP2 or EP4 cDNA [76]. Wang et al proposed the possible PGE2 downstream targets that might serve as promising specific chemopreventive agents for cancer prevention and treatment, which include angiogenic factors (VEGF, bFGF), anti-apoptotic factors (Bcal-2), chemokines (MIP-1α, MIP-1β, RANTES, CXCR4) and their receptors, and immunosuppressive mediators [7]

Conclusions

Findings

Compliance with ethical standards