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Review
. 2020 Jun;301(6):1365-1375.
doi: 10.1007/s00404-020-05559-6. Epub 2020 May 3.

COX-2-PGE2-EPs in gynecological cancers

Yao Ye  1 , Xipeng Wang  2 , Udo Jeschke  3   4 , Viktoria von Schönfeldt  5
Affiliations
Review

COX-2-PGE2-EPs in gynecological cancers

Yao Ye et al. Arch Gynecol Obstet. 2020 Jun.

Abstract

Purpose: Nonsteroidal 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.

Methods: Literature searches were performed to the function of COX-2-PGE2-EPs in gynecological malignancies.

Results: This 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.

Conclusion: EPs represent promising anti-inflammation biomarkers for gynecological cancer and may be novel treatment targets in the near future.

Keywords: Cervical cancer; Cyclooxygenase-2 (COX-2); Endometrial cancer; Ovarian cancer; Prostaglandin E2 receptors (EPs).

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Conflict of interest statement

All authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
COX-2-PGE2-EPs signaling pathway. Arachidonic acid is released from the membrane phospholipids by PLA2 and then is metabolized by COX-1 and COX-2 into PGH2. PGH2 is converted by specific isomerases (PGDS, PGES, PGFS and PGIS) and TXA synthase to multiple prostaglandins (PGE2, PGD2, PGF2α, PGI2) and the thromboxane A2 [4]. Prostaglandins act through relative receptors (EP, DP, FP, IP and TP) to mediate their effects [5]. The inhibitors of COX-2-PGE2-EPs signaling pathway include nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 selective inhibitors (COXIBs), PGES inhibitor, 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and EP inhibitors. NSAIDs inhibit the function of both COX-1 and COX-2 while COXIBs only inhibit the function of COX-2. PGE2 is degraded by 15-PGDH into an inactive 15-keto PGE2 after binding to EP receptors [6]. Both PGES inhibitors and EP inhibitors are novel inhibitors that have been investigating in these years. PLA2 phospholipases A2, COX-1 cyclooxygenase-1 COX-2 cyclooxygenase-2, PGDS prostaglandin D synthase, PGES prostaglandin G synthase, PGFS prostaglandin F synthase, PGIS prostaglandin I synthase, PG prostaglandin, EP prostaglandin E receptor, DP1.2 prostaglandin D receptor 1.2, FP prostaglandin F receptor, IP prostaglandin I receptor, ATP adenosine triphosphate, cAMP cyclic adenosine monophosphate
Fig. 2
Fig. 2
Overview the expression of COX-2-PGE2-EPs signaling in gynecological malignancies (endometrial cancer, ovarian cancer and cervical cancer). Red arrow: upregulation; green arrow:downregulation; -: uncertain
See this image and copyright information in PMC

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