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Prostaglandin Terminal Synthases As Novel Therapeutic Targets

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Prostaglandin Terminal Synthases As Novel Therapeutic Targets No. 9] Proc. Jpn. Acad., Ser. B 93 (2017) 703 Review Prostaglandin terminal synthases as novel therapeutic targets † By Shuntaro HARA*1, (Communicated by Shigekazu NAGATA, M.J.A.) Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) exert their anti-inflammatory and anti-tumor effects by reducing prostaglandin (PG) production via the inhibition of cyclooxygenase (COX). However, the gastrointestinal, renal and cardiovascular side effects associated with the pharmacological inhibition of the COX enzymes have focused renewed attention onto other potential targets for NSAIDs. PGH2, a COX metabolite, is converted to each PG species by species-specific PG terminal synthases. Because of their potential for more selective modulation of PG production, PG terminal synthases are now being investigated as a novel target for NSAIDs. In this review, I summarize the current understanding of PG terminal synthases, with a focus on microsomal PGE synthase-1 (mPGES-1) and PGI synthase (PGIS). mPGES-1 and PGIS cooperatively exacerbate inflammatory reactions but have opposing effects on carcinogenesis. mPGES-1 and PGIS are expected to be attractive alternatives to COX as therapeutic targets for several diseases, including inflammatory diseases and cancer. Keywords: prostaglandin, prostacyclin, NSAIDs, inflammatory reaction, carcinogenesis fatty acids, and they have a broad range of biological 1. Introduction activities.1) Prostanoids include what are sometimes Prostanoids are cyclic and oxygenated metabo- referred to as the “classical” prostaglandins (PGs), lites comprised of B-3 and B-6 20-carbon essential such as PGD, PGE, and PGF (all of which have a prostanoic acid backbone), as well as prostacyclin fi *1 Division of Health Chemistry, Department of Healthcare (PGI2) and thromboxane. Speci c prostanoids are and Regulatory Sciences, School of Pharmacy, Showa University, designated by a letter that indicates the type of ring Tokyo, Japan. structure, followed by a number that indicates † Correspondence should be addressed: S. Hara, Division of the number of double bonds in the hydrocarbon Health Chemistry, Department of Healthcare and Regulatory structure. Among the prostanoids, the most abun- Sciences, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan (e-mail: haras@pharm. dant are the “2-series” compounds such as PGE2 that showa-u.ac.jp). are formed from arachidonic acid (AA). Abbreviations: AA: arachidonic acid; AAV: adeno-asso- Three types of enzymes — phospholipase A2 ciated virus; ACF: aberrant crypt foci; AD: Alzheimer’s disease; (PLA2), cyclooxygenase (COX), and PG terminal AOM: azoxymethane; BLT2: leukotriene B4 receptor type-2; BM- M)s: bone marrow-derived M)s; bp: base-pair; COX: cyclo- synthase — are involved in the biosynthesis of oxygenase; cPGES: cytosolic PGE synthase; DKO: double knock- prostanoids (Fig. 1).2)–5) As the first step of this out; EP: PGE2 receptor; ER: endoplasmic reticulum; GPCR: G- biosynthesis, AA is released from the sn-2 position protein-coupled receptor; GSH: glutathione; HGF: hepatocyte growth factor; 12-HHT: 12-hydroxyheptadecatrienoic acid; HIF: of glycerophospholipids by the action of PLA2.In hypoxia-inducible factor; HRE: hypoxia-responsive element; mammals, more than 20 PLA2 enzymes have been Hsp90: heat shock protein 90; IL: interleukin; IP: PGI2 receptor; identified. Among them, cytosolic cPLA2, plays KO: knockout; LLC: Lewis lung carcinoma; LPS: lipopolysaccha- ) a critical role in the stimulus-dependent liberation ride; M : macrophage; mPGES-1: microsomal PGE synthase-1; 2) mPGES-2: microsomal PGE synthase-2; NSAIDs: non-steroidal of AA. As the second step, the liberated AA is anti-inflammatory drugs; PG: prostaglandin; PGES: PGE syn- supplied to either of the two COX isozymes, COX-1 3),4) thase; PGI2: prostacyclin; PGIS: PGI synthase; PLA2: phospho- or COX-2, to be isomerized to PGH2. Finally, lipase A2; PPAR: peroxisome proliferator-activated receptor; , , in the third step, the COX metabolite PGH2 is TNF : tumor necrosis factor ; TXA2: thromboxane A2; TXS: fi thromboxane synthase; VEGF: vascular endothelial cell growth converted to each prostanoid by speci c PG terminal factor. synthases.4),5) doi: 10.2183/pjab.93.044 ©2017 The Japan Academy 704 S. HARA [Vol. 93, Phospholipids Phospholipase A2䠄PLA2㸧 Arachidonic acid Cyclooxygenase䠄COX㸧 COX-1, COX-2 NSAIDs PGH2 PG terminal synthases PGIS PGFS, PGDS, PGES TXS PGI2 PGE 2 Other prostanoids (PGF2α, PGD2, TXA2) Fig. 1. Biosynthetic pathways of prostanoids. Arachidonic acid released from membrane phospholipids by the action of phospholipase A2 (PLA2) is converted to PGH2 by cyclooxygenase (COX), and PGH2 is then isomerized to prostanoids by each PG-specific terminal enzyme. Of the two COX enzymes, COX-1 is expressed constitutively in most tissues, and COX-2 is induced in response to various types of stimuli. NSAIDs exert both beneficial and adverse effects by reducing prostanoid production via the inhibition of COX. PGDS: PGD synthase; PGES: PGE synthase; PGFS: PGF synthase; PGIS: PGI synthase; TXS: thromboxane synthase. Non-steroidal anti-inflammatory drugs (NSAIDs) protein).8)–10) The involvement of NF-5B (nuclear exert their anti-inflammatory and anti-tumor effects factor-5B) was also reported by Yamamoto et al.11) by reducing prostanoid production via the inhibition NSAIDs exert their effects by inhibiting COX-2, but of COX.3) As mentioned above, there are two COX NSAIDs also inhibit COX-1, and as a result, the isozymes, COX-1 and COX-2. COX-1 is expressed long-term use of NSAIDs is associated with severe constitutively in most tissues and is generally respon- side effects — mainly gastrointestinal injury and sible for the immediate production of prostanoids renal irritations. After the discovery of COX-2 in that control normal physiological functions such as 1991,6),7) several pharmaceutical companies launched the maintenance of gastrointestinal or renal homeo- the development of COX-2 selective inhibitors as new stasis. COX-2 is induced in response to mitogens, NSAIDs that would have less adverse effects on the cytokines, and cellular transformation, and it medi- digestive system. These COX-2 selective inhibitors ates the delayed prostanoid generation related to showed reduced gastrointestinal complications as inflammatory reactions and carcinogenesis.6),7) expected, but several clinical trials have indicated a We investigated mechanism by which COX-2 significantly increased cardiovascular risk of these is induced, and found that certain transcription medications.12),13) The specific inhibition of COX-2 factors are involved in the induction of COX-2 alters the balance between platelet-derived throm- gene, including NF-IL6 (nuclear factor for interleu- boxane A2 (TXA2) and endothelium-derived PGI2, kin-6) and CREB (cAMP response element-binding leading to increases in the risk of thrombosis due to No. 9] Prostaglandin terminal synthases 705 Table 1. Characteristics of multiple PG terminal synthases No. of Molecular Cytogenetic amino Structural Tissue Subcellular COX* weight Phenotypes of KO mice localization acid characteristics distribution localization coupling (kDa) residues Inflamed tissues, Impaired inflammatory MAPEG Perinuclear COX-2 > mPGES-1 9q34.11 152 16 cancerous reactions, suppression family membrane COX-1 tissues, of carcinogenesis, etc. kidney PGES Glutaredoxin/ Almost all Cytosol, No mPGES-2 9q34.11 377 33 thioredoxin- - tissues Golgi preference like Almost all COX-1 > cPGES 12q13.3 160 23 - Cytosol Perinatal-lethal tissues COX-2 Suppression of Mast cells, neuroinflammation & Glutathione- microglia, COX-1 > demyelination, delayed H-PGDS 4q22.3 199 23 Cytosol S-transferase Th2 cells, COX-2 resolution of inflammation, etc. suppression of PGDS carcinogenesis, etc. Impaired sleep regulation Brain, heart, and pain sensation, L-PGDS 9q34.3 190 26 Lipocalin male genital Secreted - atherosclerosis and organs, etc. obesity, etc. Vascular High blood pressure, endothelial Cytochrome Endoplasmic COX-2 > ischemic renal disorders, PGIS PGIS 20q13.13 500 56 and smooth P450 reticulum COX-1 exacerbation of muscle cells, carcinogenesis, etc. etc. Platelets, Cytochrome bronchial Endoplasmic COX-2 > Mild hemostatic defect, TXS TXS 7q34 533 60 P450 epithelium, reticulum COX-1 impaired wound healing etc. PGFS enzymes are not included in this table. Despite the long history of research on the physiological and pathological functions of PGF2,, the identity of PGFS enzymes that catalyze PGH2 to PGF2, in vivo is unclear. Some enzymes that belong to the aldo-keto reductase (AKR) superfamily have been shown to exhibit PGFS activity. *COX coupling indicates which COX isozymes functionally couple with each PG terminal synthase to yield higher amounts of the respective products when each terminal synthase is cotransfected with either of the COX isozymes into HEK293 cells. altered vascular tone. Thus, for the development of that each synthase preferentially couples with either novel NSAIDs without adverse side effects, a more COX-1 or COX-2 as its upstream enzyme.14),15) selective modulation of prostanoid production ap- Among the PG terminal synthases, microsomal pears to be desirable. PG terminal synthases have PGE synthase-1 (mPGES-1) and PGI synthase therefore gained attention as a novel target for (PGIS) are the ones that show the greatest prefer- NSAIDs. ential coupling with COX-2, suggesting that these Multiple PG terminal synthases have been two enzymes are involved in COX-2-related diseases. identified (Table 1).4),5) In vitro analyses in which My research group is, therefore, investigating the each PG terminal synthase was cotransfected with biochemical properties and the in vivo roles of either COX isozyme into HEK293 cells revealed these two PG terminal synthases. In this review, 706 S. HARA [Vol. 93, AB+ H A P M NH3 S L V M COO- L G P S F N L Lumen S S P H P Y F R A V V A L F A A P G W E A L M W F F H L L L F I L F L Q C P V L IV S Y F III A I T II I L M L T V S II L E G A IV V M R C III I D V P K N A L M R H Q Y H T A V A V L V R A T A L Y Y I C L T I R G V T E S G V K R Q D L I Cytosol V P R P R D A II I L S R K R K C Y C-domain A Q F P G A G N P E D A L R H Fig.
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