Review TRENDS in Endocrinology and Metabolism Vol.15 No.8 October 2004 Prostaglandin receptor signalling and function in human endometrial pathology H.N. Jabbour and K.J. Sales MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The University of Edinburgh Academic Centre, 49 Little France Crescent, Edinburgh, EH16 4SB, UK Prostaglandins are bioactive lipids that exert an auto- prostaglandin, prostaglandin H2 (PGH2), by COX crine or paracrine function by binding to specific enzymes. This intermediate serves as the substrate for G-protein-coupled receptors (GPCRs) to activate intra- terminal enzymes in the prostanoid biosynthetic pathway. cellular signalling and gene transcription. Prostaglan- These enzymes are named according to the prostanoid dins are key regulators of reproductive processes, that they produce, such that PGD2 is synthesized by including ovulation, implantation and menstruation. prostaglandin D synthase (PGDS), PGF2a by PGFS, PGI2 Prostaglandins have been ascertained to have a role in (also known as prostacyclin) by PGIS, thromboxane various pathological changes of the reproductive tract (TXA2) by thromboxane synthase (TXS), and PGE2 by including menorrhagia, dysmenorrhea, endometriosis PGES [3] (Figure 1). and cancer. Although the mechanism by which prosta- At least four isoforms of PGES have been described: two glandins modulate these changes remains unclear, membrane-bound isoforms, mPGES-1 and mPGES-2; a much evidence suggests that prostaglandins and their cytosolic isoform, cPGES; and a glutathione S-transferase receptors and downstream signalling pathways are isoform, GST-m [4]. cPGES preferentially converts COX-1- involved in angiogenesis and in alterations in cell derived PGH2 to PGE2 and is associated with immediate adhesion, morphology, motility, invasion and metastases. prostaglandin biosynthesis. The inducible membrane- The potential role of prostaglandin receptors in patho- associated form, mPGES-1, is preferentially associated logical changes of the endometrium has significance for with COX-2 under conditions of limited AA supply (but the future development of therapeutic interventions. can couple to COX-1 under conditions where AA is available) and is associated with delayed biosynthesis Prostaglandins, thromboxanes and leukotrienes, collec- of PGE2 [5]. mPGES-2 is structurally distinct from tively referred to as ‘eicosanoids’, are the cyclooxygenase mPGES-1 and seems to be expressed in tissues where (COX) and lipooxygenase metabolites of arachidonic acid biosynthesis of mPGES-1 is low. mPGES-2 can couple (AA). Over the past decade, much effort has gone into with both COX-1 and COX-2. The GST-m isoform of elucidating the roles of the COX enzymes in health and PGES has been described recently; however, its speci- disease, and into creating selective COX enzyme inhibitors ficity for coupling with either COX isoform remains to as a means of therapy. Only recently has the focus turned be determined [4]. towards elucidating the function of specific prostanoid COX-1 has been long considered to be a constitutively receptors and their signalling pathways in pathology. expressed enzyme involved in normal physiological func- In this short review, we outline the role of prosta- tions, but more recently it has been shown to be glandins, their receptors and signalling pathways in upregulated in various carcinomas [6–9] and to have a pathological changes of the endometrium and explore central role in tumorigenesis [10–12].COX-2isthe the potential phenotypic effects that they might mediate product of an immediate early gene that is rapidly induced in target cells. by growth factors, oncogenes, carcinogens and tumour- promoting phorbol esters, and its involvement in rheu- matic disease, inflammation and tumorigenesis has been Cyclooxygenase enzymes demonstrated [1]. In vitro model systems of cell lines So far, three isoforms of the COX enzyme (COX-1, COX-2 overexpressing COX-2 have shown that the upregulation and COX-3) have been reported to catalyse the committed of this enzyme, coupled with the consequent increase in step in the biosynthesis of prostaglandin and thrombox- PGE2 biosynthesis, promotes angiogenesis [13], inhibits ane (collectively termed ‘prostanoids’) [1,2]. After the apoptosis [14] and increases the proliferation and meta- activation of phospholipase A2 (PLA2), AA is released static potential of epithelial cells [15]. A role for a func- from plasma membrane phospholipids or dietary fats, and is tional COX-3 isoform in human physiology and cyclized, oxygenated and reduced to the intermediary pathophysiology remains to be established. Corresponding author: H.N. Jabbour ([email protected]). The importance of COX-1 and COX-2 in reproduction has been observed from studies in knockout mice. Mice deficient www.sciencedirect.com 1043-2760/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2004.08.006 Review TRENDS in Endocrinology and Metabolism Vol.15 No.8 October 2004 399 PGE2 PGI2 PGF2α PGD2 TXA2 EP1 EP2 EP3 EP4 IPFP DP TP PGT PLA2 α α α α α α α α q s i/s/q s s/q q s i/s/q ↑↓ ↑ cAMP cAMP ↑ 2+ ↑↓ cAMP IP3/Ca ↑ 2+ IP3/Ca ↑ cAMP PGE2 AA PGI2 PGF ↑ 2+ 2α ↑ cAMP IP3/Ca PGD2 TXA2 ↑ ↑ 2+ ↑ COX IP3/Ca cAMP PGES ↑ 2+ IP3/Ca PGFS PGDS PGIS TXS Figure 1. The cyclooxygenase (COX) and prostanoid biosynthetic and signalling pathways. Arachidonic acid (AA) is released from plasma membrane phospholipids by phospholipase A2 (PLA2) and used by COX enzymes and specific synthase enzymes, such as prostaglandin D synthase (PGDS), PGES, PGFS, PGIS thromboxane synthase (TXS), to form prostaglandin D2 (PGD2), PGE2, PGF2a, PGI2 and thromboxane A2 (TXA2), respectively. These molecules are actively transported out of the cell by means of a prostaglandin transporter (PGT), where they exert an autocrine or paracrine effect by coupling to their respective heptahelical transmembrane receptors, DP, EP1–EP4, FP, IP and TP, to activate second messengers, such as cyclic AMP (cAMP) and inositol (1,4,5)-trisphosphate (IP3), and intracellular signalling cascades. in COX-1 show longer gestation periods and protracted respectively,the DP,EP,FP,IP and TP prostanoid receptors. parturition and deliver fewer live young as compared with There are four subtypes of EP receptor (EP1–EP4), which wild-type mice [16,17]. This effect is predominantly caused are encoded by four separate genes [3] (Figure 1). In by abolition of the luteolytic role of PGF2a in parturition. addition, there are several splice variants of the EP3, FP Ablation of the gene encoding COX-2 in mice results in and TP receptors, which differ only in their carboxy- multiple reproductive failures, including in ovulation, terminal tails. In general, prostanoid receptor isoforms fertilization, implantation and decidualization, confirming show similar ligand binding but differ in their signalling that the prostaglandins produced by COX-2 have a crucial pathways, their sensitivity to agonist-induced desensitiza- role in these processes [18,19]. tion, and their tendency towards constitutive activity. Phylogenetic analyses indicate that receptors shar- Prostaglandin receptors ing a common signal pathway have higher sequence After biosynthesis, prostanoids are rapidly transported homology than do receptors sharing a common prostan- out of the cell by means of a prostaglandin transporter oid as their preferential ligand. Among the different (PGT), a protein belonging to a superfamily of 12-trans- receptors, the IP, DP, EP2 and EP4 receptors increase membrane organic anion-transporting polypeptides [20,21]. the accumulation of intracellular cyclic (cAMP) via Gas PGT is responsible for the efflux of newly synthesized and have been termed ‘relaxant’ receptors because they prostaglandins [20]. Expression of PGT has not been induce smooth muscle relaxation. The TP, FP and EP1 2C verified in the human endometrium, but PGT has been receptors induce Ca mobilization via Gaq and constitute shown to be involved in the transport of various a ‘contractile’ receptor group because they cause smooth prostaglandins in the bovine endometrium [22]. muscle contraction. The remaining receptor, EP3, is Once released outside the cell, prostaglandins act in an generally associated with a decline in cAMP. This autocrine or paracrine manner on their cognate hepta- ‘inhibitory’ receptor usually stimulates smooth muscle helical transmembrane GPCRs in the vicinity of their sites contraction; depending on the splice variant and cell type, however, the EP3 receptor can also increase intracellular of production. PGD2, PGE2, PGF2a, PGI2 and TXA2 exert their biological function through interactions with, cAMP and mobilize Ca2C [3]. www.sciencedirect.com 400 Review TRENDS in Endocrinology and Metabolism Vol.15 No.8 October 2004 Prostaglandin receptor cross-communication heparin-binding EGF (HB–EGF) from its latent mem- Recent studies have shown that prostanoid receptor brane-spanning precursor in the plasma membrane. Once signalling (via EP2 and FP) to downstream signalling cleaved, the HB–EGF ligand can associate with and pathways involves productive cross-communication with activate the EGFR, and thereby induce downstream the epidermal growth factor receptor (EGFR) [23,24]. signalling events such as phosphorylation of the MAPK These data are supported by several studies providing extracellular-signal-regulated kinases 1 and 2 (ERK1/2). evidence that prostanoid GPCRs activate receptor tyro- In addition, several studies have shown that activation of sine kinases (RTKs)