COX-2-PGE2-EPs in gynecological cancers

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).

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, PGF_2α, 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

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