Prostaglandin Terminal Synthases As Novel Therapeutic Targets

Overview

Journal Proc Jpn Acad Ser B Phys Biol Sci

Specialties Biology
Science

Date 2017 Nov 14

PMID 29129850

Citations 11

Authors

Shuntaro Hara

Affiliations

Soon will be listed here.

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. PGH, 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.

Citing Articles

Spatiotemporally distinct roles of cyclooxygenase-1 and cyclooxygenase-2 at fetomaternal interface in mice.

Aikawa S, Matsuo M, Akaeda S, Sugimoto Y, Arita M, Isobe Y JCI Insight. 2024; 9(19).

PMID: 39377223 PMC: 11466189. DOI: 10.1172/jci.insight.181865.

Prostacyclin synthase deficiency exacerbates systemic inflammatory responses in lipopolysaccharide-induced septic shock in mice.

Ochiai T, Honsawa T, Yamaguchi K, Sasaki Y, Yokoyama C, Kuwata H Inflamm Res. 2024; 73(8):1349-1358.

PMID: 38832966 DOI: 10.1007/s00011-024-01902-8.

Growth of T-cell lymphoma cells is inhibited by mPGES-1/PGE2 suppression via JAK/STAT, TGF-β/Smad3 and PI3K/AKT signal pathways.

Li Y, Qiu M, Li B, Xiao J, Yang W, Xie S Transl Cancer Res. 2022; 11(7):2175-2184.

PMID: 35966330 PMC: 9372224. DOI: 10.21037/tcr-21-2834.

Phagocytes produce prostaglandin E2 in response to cytosolic Listeria monocytogenes.

McDougal C, Morrow Z, Christopher T, Kim S, Carter D, Stevenson D PLoS Pathog. 2021; 17(9):e1009493.

PMID: 34555127 PMC: 8491950. DOI: 10.1371/journal.ppat.1009493.

Prostanoids and Resolution of Inflammation - Beyond the Lipid-Mediator Class Switch.

Schmid T, Brune B Front Immunol. 2021; 12:714042.

PMID: 34322137 PMC: 8312722. DOI: 10.3389/fimmu.2021.714042.

References

Grad I, McKee T, Ludwig S, Hoyle G, Ruiz P, Wurst W . The Hsp90 cochaperone p23 is essential for perinatal survival. Mol Cell Biol. 2006; 26(23):8976-83. PMC: 1636834. DOI: 10.1128/MCB.00734-06. View

Camacho M, Rodriguez C, Guadall A, Alcolea S, Orriols M, Escudero J . Hypoxia upregulates PGI-synthase and increases PGI₂ release in human vascular cells exposed to inflammatory stimuli. J Lipid Res. 2011; 52(4):720-31. PMC: 3284164. DOI: 10.1194/jlr.M011007. View

Kosaka T, Miyata A, Ihara H, Hara S, Sugimoto T, Takeda O . Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2. Eur J Biochem. 1994; 221(3):889-97. DOI: 10.1111/j.1432-1033.1994.tb18804.x. View

Nakajima S, Honda T, Sakata D, Egawa G, Tanizaki H, Otsuka A . Prostaglandin I2-IP signaling promotes Th1 differentiation in a mouse model of contact hypersensitivity. J Immunol. 2010; 184(10):5595-603. DOI: 10.4049/jimmunol.0903260. View

Smith W, Dewitt D, Garavito R . Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem. 2000; 69:145-82. DOI: 10.1146/annurev.biochem.69.1.145. View

Nakanishi M, Menoret A, Tanaka T, Miyamoto S, Montrose D, Vella A . Selective PGE(2) suppression inhibits colon carcinogenesis and modifies local mucosal immunity. Cancer Prev Res (Phila). 2011; 4(8):1198-208. PMC: 3151318. DOI: 10.1158/1940-6207.CAPR-11-0188. View

Yokoyama C, Yabuki T, Inoue H, Tone Y, Hara S, Hatae T . Human gene encoding prostacyclin synthase (PTGIS): genomic organization, chromosomal localization, and promoter activity. Genomics. 1996; 36(2):296-304. DOI: 10.1006/geno.1996.0465. View

OCallaghan G, Houston A . Prostaglandin E2 and the EP receptors in malignancy: possible therapeutic targets?. Br J Pharmacol. 2015; 172(22):5239-50. PMC: 5341220. DOI: 10.1111/bph.13331. View

Kujubu D, Fletcher B, Varnum B, Lim R, Herschman H . TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem. 1991; 266(20):12866-72. View

10.

Nemenoff R, Meyer A, Hudish T, Mozer A, Snee A, Narumiya S . Prostacyclin prevents murine lung cancer independent of the membrane receptor by activation of peroxisomal proliferator--activated receptor gamma. Cancer Prev Res (Phila). 2009; 1(5):349-56. PMC: 2680197. DOI: 10.1158/1940-6207.CAPR-08-0145. View

11.

Tone Y, Inoue H, Hara S, Yokoyama C, Hatae T, Oida H . The regional distribution and cellular localization of mRNA encoding rat prostacyclin synthase. Eur J Cell Biol. 1997; 72(3):268-77. View

12.

Langenbach R, Morham S, Tiano H, Loftin C, Ghanayem B, Chulada P . Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell. 1995; 83(3):483-92. DOI: 10.1016/0092-8674(95)90126-4. View

13.

McAdam B, Mardini I, Kapoor S, Lawson J, FitzGerald G . Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A. 1999; 96(1):272-7. PMC: 15129. DOI: 10.1073/pnas.96.1.272. View

14.

Kuwamoto S, Inoue H, Tone Y, Izumi Y, Tanabe T . Inverse gene expression of prostacyclin and thromboxane synthases in resident and activated peritoneal macrophages. FEBS Lett. 1997; 409(2):242-6. DOI: 10.1016/s0014-5793(97)00516-4. View

15.

Ae T, Ohno T, Hattori Y, Suzuki T, Hosono K, Minamino T . Role of microsomal prostaglandin E synthase-1 in the facilitation of angiogenesis and the healing of gastric ulcers. Am J Physiol Gastrointest Liver Physiol. 2010; 299(5):G1139-46. DOI: 10.1152/ajpgi.00013.2010. View

16.

Kawakami T, Kanazawa H, Satoh T, Ieda M, Ieda Y, Kimura K . AAV-PGIS gene transfer improves hypoxia-induced pulmonary hypertension in mice. Biochem Biophys Res Commun. 2007; 363(3):656-61. DOI: 10.1016/j.bbrc.2007.09.039. View

17.

Yokoyama C, Yabuki T, Shimonishi M, Wada M, Hatae T, Ohkawara S . Prostacyclin-deficient mice develop ischemic renal disorders, including nephrosclerosis and renal infarction. Circulation. 2002; 106(18):2397-403. DOI: 10.1161/01.cir.0000034733.93020.bc. View

18.

Sugimoto Y, Narumiya S . Prostaglandin E receptors. J Biol Chem. 2007; 282(16):11613-7. DOI: 10.1074/jbc.R600038200. View

19.

Kobayashi T, Nakatani Y, Tanioka T, Tsujimoto M, Nakajo S, Nakaya K . Regulation of cytosolic prostaglandin E synthase by phosphorylation. Biochem J. 2004; 381(Pt 1):59-69. PMC: 1133762. DOI: 10.1042/BJ20040118. View

20.

Sasaki Y, Kamei D, Ishikawa Y, Ishii T, Uematsu S, Akira S . Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis. Oncogene. 2011; 31(24):2943-52. DOI: 10.1038/onc.2011.472. View