PDF herunterladen
Thromb Haemost 2006; 96(04): 417-422
DOI: 10.1160/TH06-07-0403
Theme Issue Article
Schattauer GmbH

Transcription-based COX-2 inhibition: A therapeutic strategy

Kenneth K. Wu
1   Vascular Biology Research Center and Division of Hematology, Department of Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA
› InstitutsangabenFinancial support: This work is supported by grants from National Institutes of Health, USA (P50 NS-23327 and R01 HL-50675).
Weitere Informationen

Publikationsverlauf

Received 18. Juli 2006

Accepted after revision 05. September 2006

Publikationsdatum:
29. November 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Summary

Potent selective cyclooxygenase-2 (COX-2) inhibitors are effective in controlling inflammatory disorders but are associated with cardiovascular complications. Their clinical use has been severely limited. We propose that transcription-based inhibition of COX-2 expression represents a therapeutic strategy that may circumvent the undesired complications of COX-2 inhibitors. Reported data from several laboratories including ours have identified C/EBPβ as a key transactivator mediating COX-2 transcriptional activation induced by diverse pro-inflammatory mediators. Results from our recent work show that sodium salicylate at pharmacological concentrations inhibits C/EBPβ binding to COX-2 promoter by direct inhibition of p90 ribosomal S6 kinase (RSK). RSK phosphorylates C/EBPβ and stimulates its binding to enhancer elements. We propose that RSK1/2 is a potential target for screening drugs with novel anti-inflammatory and anti-neoplastic therapeutic potentials.

Keywords

Cyclooxygenase-2 - inflammation - C/EBPβ,aspirin - P90 ribosomal S6 kinase
 

  • References

  • 1 Wu KK. Inducible cyclooxygenase and nitric oxide synthase. Adv Pharmacol 1995; 33: 179-207.
    PubMedGoogle Scholar
  • 2 Fletcher BS, Kujubu DA, Perrin DM. et al. Structure of the mitogen-inducible TIS10 gene and demonstration that the TIS10-encoded protein is a functional prostaglandin G/H synthase. J Biol Chem 1992; 267: 4338-44.
    PubMedGoogle Scholar
  • 3 Tazawa R, Xu XM, Wu KK. et al. Characterization of the genomic structure, chromosomal location and promoter of human prostaglandin H synthase-2 gene. Biochem Biophys Res Commun 1994; 203: 190-9.
    CrossrefPubMedGoogle Scholar
  • 4 Liou JY, Shyue SK, Tsai MJ. et al. Colocalization of prostacyclin synthase with prostaglandinH synthase-1 (PGHS-1) but not phorbol ester-induced PGHS-2 in cultured endothelial cells. J Biol Chem 2000; 275: 15314-20.
    CrossrefPubMedGoogle Scholar
  • 5 Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. J Biol Chem 1996; 271: 33157-60.
    CrossrefPubMedGoogle Scholar
  • 6 Cipollone F, Prontera C, Pini B. et al. Overexpression of functionally coupled cyclooxygenase-2 and prostaglandinE synthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E(2)-dependent plaque instability. Circulation 2001; 104: 921-7.
    CrossrefPubMedGoogle Scholar
  • 7 Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 1978; 30: 293-331.
    PubMedGoogle Scholar
  • 8 Liou JY, Lee S, Ghelani D. et al. Protection of Endothelial Survival by Peroxisome Proliferator-Activated Receptor-{delta Mediated 14-3-3 Upregulation. Arterioscler Thromb Vasc Biol. 2006 (in press).
    PubMedGoogle Scholar
  • 9 FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004; 351: 1709-11.
    CrossrefPubMedGoogle Scholar
  • 10 Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. J Am Med Assoc 2001; 286: 954-9.
    CrossrefPubMedGoogle Scholar
  • 11 McAdam BF, Catella-Lawson F, Mardini IA. et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology ofa selective inhibitor of COX-2. Proc Natl Acad Sci USA 1999; 96: 272-7.
    CrossrefPubMedGoogle Scholar
  • 12 FitzGerald GA, Smith B, Pedersen AK. et al. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med 1984; 310: 1065-8.
    CrossrefPubMedGoogle Scholar
  • 13 Belton O, Byrne D, Kearney D. et al. Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis. Circulation 2000; 102: 840-5.
    CrossrefPubMedGoogle Scholar
  • 14 Cheng Y, Austin SC, Rocca B. et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 2002; 296: 539-41.
    CrossrefPubMedGoogle Scholar
  • 15 Lim H, Gupta RA, Ma WG. et al. Cyclooxygenase2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta. Genes Dev 1999; 13: 1561-74.
    CrossrefPubMedGoogle Scholar
  • 16 Huang JC, Wun WS, Goldsby JS. et al. Cyclooxygenase-2-derived endogenous prostacyclin enhances mouse embryo hatching. Hum Reprod 2004; 19: 2900-6.
    CrossrefPubMedGoogle Scholar
  • 17 Hao CM, Komhoff M, Guan Y. et al. Selective targeting of cyclooxygenase-2 reveals its role in renal medullary interstitial cell survival. Am J Physiol 1999; 277: F352-F359.
    PubMedGoogle Scholar
  • 18 Adderley SR, Fitzgerald DJ. Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases -mediated induction of cyclooxygenase-2. J Biol Chem 1999; 274: 5038-46.
    CrossrefPubMedGoogle Scholar
  • 19 Herschman HR. Prostaglandin synthase 2. Biochim Biophys Acta 1996; 1299: 125-40.
    CrossrefPubMedGoogle Scholar
  • 20 Wadleigh DJ, Reddy ST, Kopp E. et al. Transcriptional activation of the cyclooxygenase-2 gene in endotoxin-treated RAW 264.7 macrophages. J Biol Chem 2000; 275: 6259-66.
    CrossrefPubMedGoogle Scholar
  • 21 Schroer K, Zhu Y, Saunders MA. et al. Obligatory role of cyclic adenosine monophosphate response element in cyclooxygenase-2 promoter induction and feedback regulation by inflammatory mediators. Circulation 2002; 105: 2760-5.
    CrossrefPubMedGoogle Scholar
  • 22 Deng WG, Zhu Y, Wu KK. Up-regulation of p300 binding and p50 acetylation in tumor necrosis factoralpha-induced cyclooxygenase-2 promoter activation. J Biol Chem 2003; 278: 4770-7.
    CrossrefPubMedGoogle Scholar
  • 23 Deng WG, Zhu Y, Wu KK. Role of p300 and PCAF in regulating cyclooxygenase-2 promoter activation by inflammatory mediators. Blood 2004; 103: 2135-42.
    CrossrefPubMedGoogle Scholar
  • 24 Inoue H, Nanayama T, Hara S. et al. The cyclic AMP response element plays an essential role in the expression of the human prostaglandin-endoperoxide synthase 2 gene in differentiated U937 monocytic cells. FEBS Lett 1994; 15: 51-4.
    PubMedGoogle Scholar
  • 25 Hernandez GL, Volpert OV, Iniguez MA. et al. Selective inhibition of vascular endothelial growth factormediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2. J Exp Med 2001; 193: 607-20.
    CrossrefPubMedGoogle Scholar
  • 26 Thomas B, Berenbaum F, Humbert L. et al. Critical role of C/EBPdelta and C/EBPbeta factors in the stimulation of the cyclooxygenase-2 gene transcription by interleukin-1beta in articular chondrocytes. Eur J Biochem 2000; 267: 6798-809.
    CrossrefPubMedGoogle Scholar
  • 27 Mestre JR, Mackrell PJ, Rivadeneira DE. et al. Redundancy in the signaling pathways and promoter elements regulating cyclooxygenase-2 gene expression in endotoxin-treated macrophage/monocytic cells. J Biol Chem 2001; 276: 3977-82.
    CrossrefPubMedGoogle Scholar
  • 28 Caivano M, Gorgoni B, Cohen P. et al. The induction of cyclooxygenase-2 mRNA in macrophages is biphasic and requires both CCAAT enhancer-binding protein beta (C/EBP beta) and C/EBP delta transcription factors. J Biol Chem 2001; 276: 48693-701.
    CrossrefPubMedGoogle Scholar
  • 29 Eliopoulos AG, Dumitru CD, Wang CC. et al. Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals. EMBO J 2002; 21: 4831-40.
    CrossrefPubMedGoogle Scholar
  • 30 Reddy ST, Wadleigh DJ, Herschman HR. Transcriptional regulation of the cyclooxygenase-2 gene in activated mast cells. J Biol Chem 2000; 275: 3107-13.
    CrossrefPubMedGoogle Scholar
  • 31 Yamamoto K, Arakawa T, Ueda N. et al. Transcriptional roles of nuclear factor kappa B and nuclear factor-interleukin-6 in the tumor necrosis factor alpha-dependent induction of cyclooxygenase-2 in MC3T3-E1 cells. J Biol Chem 1995; 270: 31315-20.
    CrossrefPubMedGoogle Scholar
  • 32 Inoue H, Yokoyama C, Hara S. et al. Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular endothelial cells. J Biol Chem 1995; 270: 24965-71.
    CrossrefPubMedGoogle Scholar
  • 33 Wu KK, Liou JY, Cieslik K. Transcriptional Control of COX-2 via C/EBPbeta. Arterioscler Thromb Vasc Biol 2005; 25: 679-85.
    CrossrefPubMedGoogle Scholar
  • 34 Chen J, Zhao M, Rao R. et al. C/EBPβ and its binding element are required for NFκB-induced COX2 expression following hypertonic stress. J Biol Chem 2005; 280: 16354-9.
    CrossrefPubMedGoogle Scholar
  • 35 Sorli CH, Zhangdagger H-J, Armstrongdagger MB. et al. Basal expression of cyclooxygenase-2 and nuclear factor-interleukin 6 are dominant and coordinately regulated by interleukin 1 in the pancreatic islet. Proc Natl 1998; 95: 1788-93.
    PubMedGoogle Scholar
  • 36 Ogasawara A, Arakawa T, Kaneda T. et al. Fluid shear stress-induced cyclooxygenase-2 expression is mediated by C/EBP beta, cAMP-response elementbinding protein, and AP-1 in osteoblastic MC3T3-E1 cells. J Biol Chem 2001; 276: 7048-54.
    CrossrefPubMedGoogle Scholar
  • 37 Wedel A, Ziegler-Heitbrock HW. The C/EBP family of transcription factors. Immunobiology 1995; 193: 171-85.
    CrossrefPubMedGoogle Scholar
  • 38 Akira S, Kishimoto TNF. IL6 and NF-kappa B in cytokine gene regulation. Adv Immunol 1997; 65: 1-46.
    PubMedGoogle Scholar
  • 39 Zhu Y, Saunders MA, Yeh H. et al. Dynamic regulation of cyclooxygenase-2 promoter activity by isoforms of CCAAT/enhancer-binding proteins. J Biol Chem 2002; 277: 6923-8.
    CrossrefPubMedGoogle Scholar
  • 40 Eberhart CE, Coffey RJ, Radhika A. et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994; 107: 1183-8.
    CrossrefPubMedGoogle Scholar
  • 41 Kargman SL, O’Neill GP, Vickers PJ. et al. Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. Cancer Res 1995; 55: 2556-9.
    PubMedGoogle Scholar
  • 42 Sano H, Kawahito Y, Wilder RL. et al. Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res 1995; 55: 3785-9.
    PubMedGoogle Scholar
  • 43 Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 1995; 83: 493-501.
    CrossrefPubMedGoogle Scholar
  • 44 Tsujii M, Kawano S, DuBois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 1997; 94: 3336-40.
    CrossrefPubMedGoogle Scholar
  • 45 Kutchera W, Jones DA, Matsunami N. et al. Prostaglandin H synthase 2 is expressed abnormally in human colon cancer: evidence for a transcriptional effect. Proc Natl Acad Sci USA 1996; 93: 4816-20.
    CrossrefPubMedGoogle Scholar
  • 46 Shao J, Sheng H, Inoue H. et al. Regulation of constitutive cyclooxygenase-2 expression in colon carcinoma cells. J Biol Chem 2000; 275: 33951-6.
    CrossrefPubMedGoogle Scholar
  • 47 Kim Y, Fischer SM. Transcriptional regulation of cyclooxygenase-2 in mouse skin carcinoma cells. J Biol Chem 1998; 273: 27686-94.
    CrossrefPubMedGoogle Scholar
  • 48 Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 1994; 265: 956-9.
    CrossrefPubMedGoogle Scholar
  • 49 Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998; 396: 7-80.
    PubMedGoogle Scholar
  • 50 Frantz B, O’Neill EA. The effect of sodium salicylate and aspirin on NF-kappa B. Science 1995; 270: 2017-9.
    CrossrefPubMedGoogle Scholar
  • 51 Xu XM, Sansores-Garcia L, Chen XM. et al. Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate. Proc Natl Acad Sci USA 1999; 96: 5292-7.
    CrossrefPubMedGoogle Scholar
  • 52 Saunders MA, Sansores-Garcia L, Gilroy DW. et al. Selective suppression of CCAAT/enhancer-binding protein beta binding and cyclooxygenase-2 promoter activity by sodium salicylate in quiescent human fibroblasts. J Biol Chem 2001; 276: 18897-904.
    CrossrefPubMedGoogle Scholar
  • 53 Cieslik K, Zhu Y, Wu KK. Salicylate suppresses macrophage NOS-2 and COX-2 expression by inhibiting C/EBPßbinding viaa common signaling pathway. J Biol Chem 2002; 277: 49304-10.
    CrossrefPubMedGoogle Scholar
  • 54 Nakajima T, Kinoshita S, Sasagawa T. et al. Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. Proc Natl Acad Sci USA 1993; 90: 2207-11.
    CrossrefPubMedGoogle Scholar
  • 55 Trautwein C, Caelles C, van der Geer P. et al. Transactivation by NF-IL6/LAP is enhanced by phosphorylation of its activation domain. Nature 1993; 364: 544-7.
    CrossrefPubMedGoogle Scholar
  • 56 Buck M, Poli V, van der Geer P. et al. Phosphorylation of rat serine 105 or mouse threonine 217 in C/EBP beta is required for hepatocyte proliferation induced by TGF alpha. Mol Cell 1999; 04: 1087-92.
    CrossrefPubMedGoogle Scholar
  • 57 Wegner M, Cao Z, Rosenfeld MG. Calcium-regulated phosphorylation within the leucine zipper of C/EBP beta. Science 1992; 256: 370-3.
    CrossrefPubMedGoogle Scholar
  • 58 Cieslik KA, Zhu Y, Shtivelband M. et al. Inhibition of p90 ribosomal S6 kinase-mediated CCAAT/enhancer-binding protein beta activation and cyclooxygenase-2 expression by salicylate. J Biol Chem 2005; 280: 18411-7.
    CrossrefPubMedGoogle Scholar
  • 59 Itoh S, Ding B, Shishido T. et al. Role of p90 ribosomal S6 kinase-mediated prorenin-converting enzyme in ischemic and diabetic myocardium. Circulation 2006; 113: 1787-98.
    CrossrefPubMedGoogle Scholar
  • 60 Clark DE, Errington TM, Smith JA. et al. The serine/threonine protein kinase, p90 ribosomal S6 kinase, is an important regulator of prostate cancer cell proliferation. Cancer Res 2005; 65: 3108-16.
    CrossrefPubMedGoogle Scholar
  • 61 Subbaramaiah K, Chung WJ, Michaluart P. et al. Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. J Biol Chem 1998; 273: 21875-82.
    CrossrefPubMedGoogle Scholar
  • 62 Liang YC, Huang YT, Tsai SH. et al. Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. Carcinogenesis 1999; 20: 1945-52.
    CrossrefPubMedGoogle Scholar
  • 63 Shimamura A, Ballif BA, Richards SA. et al. Rsk1 mediates a MEK-MAP kinase cell survival signal. J Curr Biol 2000; 10: 127-35.
    CrossrefPubMedGoogle Scholar
  • 64 Abe J, Okuda M, Huang Q. et al. Reactive oxygen species activate p90 ribosomal S6 kinase via Fyn and Ras. J Biol Chem 2000; 275: 1739-48.
    CrossrefPubMedGoogle Scholar
  • 65 Itoh S, Ding B, Bains CP. et al. Role of p90 ribosomal S6 kinase (p90RSK) in reactive oxygen species and protein kinase C beta (PKC-beta)-mediated cardiac troponin I phosphorylation. J Biol Chem 2005; 280: 24135-42.
    CrossrefPubMedGoogle Scholar
  • 66 Chen RH, Chung J, Blenis J. Regulation of pp90rsk phosphorylation and S6 phosphotransferase activity in Swiss 3T3 cells by growth factor-, phorbol ester-, and cyclic AMP-mediated signal transduction. Mol Cell Biol 1991; 11: 1861-7.
    CrossrefPubMedGoogle Scholar
  • 67 Xing J, Ginty DD, Greenberg ME. Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 1996; 273: 959-63.
    CrossrefPubMedGoogle Scholar
  • 68 Ghoda L, Lin X, Greene WC. The 90-kDa ribosomal S6 kinase (pp90rsk) phosphorylates the N-terminal regulatory domain of IkappaBalpha and stimulates its degradation in vitro . J Biol Chem 1997; 272: 21281-8.
    CrossrefPubMedGoogle Scholar
  • 69 Schouten GJ, Vertegaal AC, Whiteside ST. et al. IkappaB alpha is a target for the mitogen-activated 90 kDa ribosomal S6 kinase. EMBO J 1997; 16: 3133-44.
    CrossrefPubMedGoogle Scholar
  • 70 Descombes P, Schibler UA. liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA. Cell 1991; 67: 569-79.
    CrossrefPubMedGoogle Scholar
  • 71 Dixit V. NF-κB Signaling: Many roads lead to Mad-rid. Cell 2002; 111: 615-9.
    CrossrefPubMedGoogle Scholar
  • 72 Karin M. The beginning of the end: Ikappa B kinase (IKK) and NF-kappa B activation. J Biol Chem 1999; 274: 27339-42.
    CrossrefPubMedGoogle Scholar