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The Role of Prostaglandins and Other Eicosanoids in the Gastrointestinal Tract

2005; Elsevier BV; Volume: 128; Issue: 5 Linguagem: Inglês

10.1053/j.gastro.2004.09.080

1528-0012

Dingzhi Wang, Jason R. Mann, Raymond N. DuBois,

Cancer, Lipids, and Metabolism

Nonsteroidal anti-inflammatory drugs (NSAIDs) are generally prescribed to ameliorate symptoms associated with acute pain and chronic inflammatory diseases such as arthritis. Recent epidemiologic studies and clinical trials indicate that use of NSAIDs and cyclooxygenase (COX)-2 selective inhibitors are associated with a reduced risk of certain malignancies, especially gastrointestinal cancer. The cyclooxygenase enzymes are the best known targets of NSAIDs; this diverse class of compounds blocks conversion of arachidonic acid to prostanoids. Prostaglandins and other eicosanoids derived from COX-1 and COX-2 are involved in a variety of physiologic and pathologic processes in the gastrointestinal tract. Recent efforts to identify the molecular mechanisms by which COX-2-derived prostanoids exert their proneoplastic effects have provided a rationale for the possible use of NSAIDs alone or in a combination with conventional or experimental anticancer agents for the treatment or prevention of gastrointestinal cancers. Nonsteroidal anti-inflammatory drugs (NSAIDs) are generally prescribed to ameliorate symptoms associated with acute pain and chronic inflammatory diseases such as arthritis. Recent epidemiologic studies and clinical trials indicate that use of NSAIDs and cyclooxygenase (COX)-2 selective inhibitors are associated with a reduced risk of certain malignancies, especially gastrointestinal cancer. The cyclooxygenase enzymes are the best known targets of NSAIDs; this diverse class of compounds blocks conversion of arachidonic acid to prostanoids. Prostaglandins and other eicosanoids derived from COX-1 and COX-2 are involved in a variety of physiologic and pathologic processes in the gastrointestinal tract. Recent efforts to identify the molecular mechanisms by which COX-2-derived prostanoids exert their proneoplastic effects have provided a rationale for the possible use of NSAIDs alone or in a combination with conventional or experimental anticancer agents for the treatment or prevention of gastrointestinal cancers. Nonsteroidal anti-inflammatory drugs (NSAIDs) are thought to exert their anti-inflammatory, analgesic, and antipyretic effects mainly by inhibiting the biosynthesis of prostaglandins.1Vane J.R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.Nature. 1971; 231: 232-235Google Scholar Because prostaglandin H synthases (commonly referred to as cyclooxygenases) catalyze the rate-limiting step in prostaglandin synthesis from arachidonic acid, one plausible mechanism for the anti-inflammatory, analgesic, and antineoplastic effects of NSAIDs is their inhibition of eicosanoid formation. When tissues are exposed to diverse physiologic and pathologic stimuli, polyunsaturated fatty acids such as arachidonic acid are liberated from membrane phospholipids by the action of phospholipase A2. Arachidonic acid can be metabolized through 1 of 3 major pathways: the cyclooxygenase pathway, the lipoxygenase pathway, or the cytochrome P-450 monooxygenase pathway. In the cyclooxygenase (COX) pathway, free arachidonic acid is converted to a variety of eicosanoids, including prostaglandins (PGs) and thromboxanes (TXs), by the prostaglandin biosynthetic machinery2Herschman H.R. Prostaglandin synthase 2.BBA. 1996; 1299: 125-140Google Scholar, 3DuBois R.N. Abramson S.B. Crofford L.R.A.G. Simon L.S. Van De Putte L.B. Lipsky P.E. Cyclooxygenase in biology and disease.FASEB J. 1998; 12: 1063-1073Crossref Scopus (2251) Google Scholar, 4Herschman H.R. Xie W. Reddy S. Inflammation, reproduction, cancer and all that The regulation and role of the inducible prostaglandin synthase.Bioessays. 1995; 17: 1031-1037Scopus (81) Google Scholar, 5Smith W.L. DeWitt D.L. Garavito R.M. Cyclooxygenases structural, cellular, and molecular biology.Annu Rev Biochem. 2000; 69: 145-182Google Scholar (Figure 1). The key regulatory step in this process is the enzymatic conversion of arachidonate to PGG2, which is then reduced to an unstable endoperoxide intermediate, PGH2. Specific PG synthases in turn metabolize PGH2 to at least 5 structurally related bioactive lipid molecules, including PGE2, PGD2, PGF2α, PGI2, and thromboxane A2 (TXA2), in a cell type-specific manner. For example, cytosolic or microsomal PGE2 synthases are able to convert PGH2 to PGE2. Two cytosolic PGE2 synthases include cytosolic glutathione transferases (GSTM2-2 and GSTM3-3), which catalyze the conversion of PGH2 to PGE2 in the human brain in a thiol-dependent manner.6Beuckmann C.T. Fujimori K. Urade Y. Hayaishi O. Identification of mu-class glutathione transferases M2-2 and M3-3 as cytosolic prostaglandin E synthases in the human brain.Neurochem Res. 2000; 25: 733-738Google Scholar The microsomal PGE2 synthases, characterized to date, include mPGES1 and mPGES2. mPGES1 exhibits a higher catalytic activity than the other PGES isomerases, indicating that it likely plays a key role in the synthesis of PGE2 from PGH2.7Jakobsson P.J. Thoren S. Morgenstern R. Samuelsson B. Identification of human prostaglandin E synthase a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target.Proc Natl Acad Sci U S A. 1999; 22: 7220-7225Google Scholar, 8Lazarus M. Munday C.J. Eguchi N. Matsumoto S. Killian G.J. Kubata B.K. Urade Y. Immunohistochemical localization of microsomal PGE synthase-1 and cyclooxygenases in male mouse reproductive organs.Endocrinology. 2002; 143: 2410-2419Google Scholar There are 2 cyclooxygenase isoforms commonly referred to as COX-1 and COX-2 for the temporal order of their discovery. Although both COX-1 and COX-2 are up-regulated in a variety of circumstances, normally, COX-1 is constitutively expressed in a broad range of cells and tissues. COX-1 expression remains constant under most physiologic or pathologic conditions, and COX-1-derived prostaglandins are thought to play a role in many normal physiologic processes. In the gut, COX-1-derived PGs play an important role in protecting the gastroduodenal mucosa from injury. Most studies indicate that COX-1-derived PGs are produced by epithelial and stromal cells in subepithelial tissues of the colon.9Craven P.A. DeRubertis F.R. Patterns of prostaglandin synthesis and degradation in isolated superficial and proliferative colonic epithelial cells compared to residual colon.Prostaglandins. 1983; 26: 583-604Google Scholar, 10Smith G.S. Warhurst G. Turnberg L.A. Synthesis and degradation of prostaglandins E2 in the epithelial and subepithelial layers of the rat intestine.BBA. 1982; 713: 684-687Google Scholar, 11Lawson L.D. Powell D.W. Bradykinin-stimulated eicosanoid synthesis and secretion by rabbit ileal components.Am J Physiol. 1987; 252: G783-G790Google Scholar For example, PGI2 is a major prostaglandin product in the gastrointestinal tract12LeDuc L.E. Needleman P. 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Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2-mediated induction of cyclooxygenase-2.J Biol Chem. 1999; 274: 5038-5046Google Scholar COX-2, by contrast, is an immediate-early response gene normally absent from most cells but highly inducible in response to inflammatory stimuli, including endotoxin, cytokines, hormones, and tumor promoters.3DuBois R.N. Abramson S.B. Crofford L.R.A.G. Simon L.S. Van De Putte L.B. Lipsky P.E. Cyclooxygenase in biology and disease.FASEB J. 1998; 12: 1063-1073Crossref Scopus (2251) Google Scholar For example, transforming growth factor-α (TGF-α), oncogenic Ha-Ras, and the tumor promoter tetradecanoyl phorbol acetate (TPA) have been shown to induce COX-2 expression and stimulate the production of PGs in normal rat intestinal epithelial (RIE-1) cells and in some human colorectal carcinoma cells.16DuBois R.N. Awad J. Morrow J. Roberts L.J. Bishop P.R. Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor-α and phorbol ester.J Clin Invest. 1994; 93: 493-498Google Scholar, 17Coffey R.J. Hawkey C.J. Damstrup L. Graves-Deal R. Daniel V.C. Dempsey P.J. DuBois R.N. Jetton T. Morrow J. EGF receptor activation induces nuclear targeting of COX-2, basolateral release of prostaglandins and mitogenesis in polarizing colon cancer cells.Proc Natl Acad Sci U S A. 1997; 94: 657-662Google Scholar, 18Sheng H. Williams C.S. Shao J. Liang P. DuBois R.N. Beauchamp R.D. Induction of cyclooxygenase-2 by activated Ha-ras in rat-1 fibroblasts and the role of the MAPK pathway.J Biol Chem. 1998; 273: 22515-22518Google Scholar Bombesin, a homolog of gastrin-releasing peptide (GRP), stimulates COX-2 expression and release of PGE2 in intestinal epithelial cells through multiple AP-1 and ERK5-dependent pathways.19Guo Y.S. Cheng J.Z. Jin G.F. Gutkind J.S. Hellmich M.R. Townsend Jr, C.M. Gastrin stimulates cyclooxygenase-2 expression in intestinal epithelial cells through multiple signaling pathways Evidence for involvement of ERK5 kinase and transactivation of the epidermal growth factor receptor.J Biol Chem. 2002; 277: 48755-48763Google Scholar Finally, gastrin and K-Ras also regulate COX-2 expression in certain contexts.20Stachura J. Konturek J.W. Dembinski A. Domschke W. Growth markers in the human gastric mucosa during adaptation to continued aspirin administration.J Clin Gastroenterol. 1996; 22: 282-287Google Scholar, 21Konturek P.C. Kania J. Kukharsky V. Ocker S. Hahn E.G. Konturek S.J. Influence of gastrin on the expression of cyclooxygenase-2, hepatocyte growth factor and apoptosis-related proteins in gastric epithelial cells.J Physiol Pharmacol. 2003; 54: 17-32Google Scholar, 22Sheng H. Shao J. Dubois R.N. 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PPARδ is an APC-regulated target of nonsteroidal anti-inflammatory drugs.Cell. 1999; 99: 335-345Google Scholar Emerging data suggest that COX-2 is one of the targets of Tcf/Lef in mouse colonic epithelial cells.24Goss K.H. Groden J. Biology of the adenomatous polyposis coli tumor suppressor.J Clin Oncol. 2000; 18: 1967-1979Crossref Scopus (331) Google Scholar, 25Mei J.M. Hord N.G. Winterstein D.F. Donald S.P. Phang J.M. Differential expression of prostaglandin endoperoxide H synthase-2 and formation of activated β-catenin-LEF-1 transcription complex in mouse colonic epithelial cells contrasting in Apc.Carcinogenesis. 1999; 20: 737-740Google Scholar Both increased Wnt-1 expression and loss of APC function can activate a common signaling pathway involving transcriptional activation mediated by β-catenin/Tcf complexes. Over-expression of oncogenic Wnt-1 in the mouse mammary epithelial lines RAC311 and C57MG induces COX-2 expression,26Howe L.R. Subbaramaiah K. Chung W.J. Dannenberg A.J. Brown A.M. Transcriptional activation of cyclooxygenase-2 in Wnt-1-transformed mouse mammary epithelial cells.Cancer Res. 1999; 59: 1572-1577Google Scholar and transgenic mice over-expressing Wnt-1 in the breast develop mammary tumors with elevated COX-2 expression.27Howe L.R. Crawford H.C. Subbaramaiah K. Hassell J.A. Dannenberg A.J. Brown A.M. PEA3 is up-regulated in response to WNT1 and activates the expression of cyclooxygenase-2.J Biol Chem. 2001; 26: 26Google Scholar, 28Schroeder J.A. Adriance M.C. McConnell E.J. Thompson M.C. Pockaj B. Gendler S.J. ErbB-β-catenin complexes are associated with human infiltrating ductal breast and murine mammary tumor virus (MMTV)-Wnt-1 and MMTV-c-Neu transgenic carcinomas.J Biol Chem. 2002; 277: 22692-22698Google Scholar Others have shown that over-expression of Wnt-3 or mutant β-catenin also lead to an increase in COX-2 expression.29Haertel-Wiesmann M. Liang Y. Fantl W.J. Williams L.T. Regulation of COX-2 and periostin by Wnt-3 in mouse mammary epithelial cells.J Biol Chem. 2000; 275: 32046-32051Scopus (93) Google Scholar, 30Araki Y. Okamura S. Hussain S.P. Nagashima M. He P. Shiseki M. Miura K. Harris C.C. Regulation of cyclooxygenase-2 expression by the Wnt and ras pathways.Cancer Res. 2003; 63: 728-734Google Scholar Finally, the PEA3 family of transcription factors may mediate Wnt-1 and APC signaling to activate COX-2 transcription through binding the NF-IL6 site in the COX-2 promoter.27Howe L.R. Crawford H.C. Subbaramaiah K. Hassell J.A. Dannenberg A.J. Brown A.M. PEA3 is up-regulated in response to WNT1 and activates the expression of cyclooxygenase-2.J Biol Chem. 2001; 26: 26Google Scholar Collectively, these data support the hypothesis that COX-2 is a downstream target of the β-catenin/Tcf signaling pathway. Increased levels of COX-2-derived prostaglandins not only mediate acute inflammatory responses but are also involved in a variety of other pathophysiologic processes, including tumor promotion, tumor-associated angiogenesis, and thrombosis. Prostaglandins exert their cellular functions by binding cell surface receptors that belong to the family of 7 transmembrane G-protein-coupled rhodopsin-type receptors. These cell surface receptors are designated DP for the PGD2 receptor, EP (EP1, EP2, EP3, and EP4) for the PGE2 receptors, FP for the PGF2α receptor, IP for the PGI2 receptor, and TP for the TXA2 receptor. The action of prostaglandins is associated with changes in the levels of second messengers.31Breyer R.M. Bagdassarian C.K. Myers S.A. 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Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration.Proc Natl Acad Sci U S A. 2001; 98: 8885-8890Google Scholar A more recent study reported that EP2 is expressed in mouse gastrointestinal epithelial cells and is up-regulated following radiation injury.40Houchen C.W. Sturmoski M.A. Anant S. Breyer R.M. Stenson W.F. Prosurvival and antiapoptotic effects of PGE2 in radiation injury are mediated by EP2 receptor in intestine.Am J Physiol Gastrointest Liver Physiol. 2003; 284: G490-G498Crossref Scopus (64) Google Scholar In this study, it was observed that PGE2 blocks crypt cell apoptosis induced by radiation through binding to EP2. DP mRNA was also detected in mucous-secreting goblet cells and the columnar epithelium of the stomach, intestine, and colon by in situ hybridization.41Wright D.H. Nantel F. Metters K.M. Ford-Hutchinson A.W. 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Cyclo-oxygenase 2 inhibitors emerging roles in the gut.Int J Colorectal Dis. 2003; 18: 279-291Google Scholar Highly selective COX-2 inhibitors, therefore, serve as useful anti-inflammatory agents with lower gastrointestinal toxicity, which may have some utility in the chemoprevention and/or treatment of colorectal, esophageal, and gastric cancers. However, it must be emphasized that the COX-1 “good”/COX-2 “bad” hypothesis is oversimplified and does not hold under all circumstances. Colorectal cancer (CRC) is a significant health concern in most industrialized countries. At least 3 major forms of CRC have been described: hereditary, sporadic, and colitis-associated CRC. More than 150,000 new cases result in 55,000 deaths annually in the United States alone. The cumulative lifetime prevalence of colorectal adenomas is 40%; approximately 10% of these “polyps” will ultimately progress to malignancy. 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