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COX-1 is coupled with mPGES-1 and ABCC4 in human cervix cancer cells

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Abstract

Cyclooxygenases are key enzymes in the arachidonic acid metabolism. Their unstable intermediate, prostaglandin H2, is further metabolized to bioactive lipids by various downstream enzymes. In this study, utilizing short hairpin RNAs, we prepared a cell line of human cervix carcinoma with stable down-regulated cyclooxygenase-1 (COX-1) to assess the impact of COX-1 reduction on the downstream enzymes. We found a significant microsomal prostaglandin E synthase-1 (mPGES-1) suppression. In addition, mRNA expression of multidrug resistance protein 4 (MRP4, ABCC4), supposed to take part in antiviral and anticancer drug transport from cells, was up-regulated after COX-1 down-regulation. Our findings indicate that mPGES-1, believed to be coexpressed preferentially with cyclooxygenase-2, may be coupled to COX-1. ABCC4 up-regulation further supports the assumption of its involvement in prostanoid transport.

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Abbreviations

COX:

Cyclooxygenase

mPGES:

Microsomal prostaglandin E synthase

MRP4:

Multidrug resistance protein 4

ABCC4:

ATP-binding cassette, sub-family C, member 4

NSAIDs:

Nonsteroidal anti-inflammatory drugs

AA:

Arachidonic acid

PG:

Prostaglandin

PGES:

Prostaglandin E synthase

cPGES:

Cytosolic prostaglandin E synthase

shRNA:

Short hairpin RNA

References

  1. Vane JR (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 231:232–235

    CAS  PubMed  Google Scholar 

  2. Dubois RN, Abramson SB, Crofford L et al (1998) Cyclooxygenase in biology and disease. FASEB J 12:1063–1073

    CAS  PubMed  Google Scholar 

  3. Ueno N, Takegoshi Y, Kamei D et al (2005) Coupling between cyclooxygenases and terminal prostanoid synthases. Biochem Biophys Res Commun 338:70–76. doi:10.1016/j.bbrc.2005.08.152

    Article  CAS  PubMed  Google Scholar 

  4. Yu Y, Fan J, Hui Y et al (2007) Targeted cyclooxygenase gene (ptgs) exchange reveals discriminant isoform functionality. J Biol Chem 282:1498–1506. doi:10.1074/jbc.M609930200

    Article  CAS  PubMed  Google Scholar 

  5. Jakobsson PJ, Thoren S, Morgenstern R et al (1999) Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci USA 96:7220–7225. doi:10.1073/pnas.96.13.7220

    Article  CAS  PubMed  Google Scholar 

  6. Tanikawa N, Ohmiya Y, Ohkubo H et al (2002) Identification and characterization of a novel type of membrane-associated prostaglandin E synthase. Biochem Biophys Res Commun 291:884–889. doi:10.1006/bbrc.2002.6531

    Article  CAS  PubMed  Google Scholar 

  7. Tanioka T, Nakatani Y, Semmyo N et al (2000) Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis. J Biol Chem 275:32775–32782. doi:10.1074/jbc.M003504200

    Article  CAS  PubMed  Google Scholar 

  8. Murakami M, Nakatani Y, Tanioka T et al (2002) Prostaglandin E synthase. Prostaglandins Other Lipid Mediat 68–69:383–399. doi:10.1016/S0090-6980(02)00043-6

    Article  PubMed  Google Scholar 

  9. Murakami M, Naraba H, Tanioka T et al (2000) Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem 275:32783–32792. doi:10.1074/jbc.M003505200

    Article  CAS  PubMed  Google Scholar 

  10. Boulet L, Ouellet M, Bateman KP et al (2004) Deletion of microsomal prostaglandin E2 (PGE2) synthase-1 reduces inducible and basal PGE2 production and alters the gastric prostanoid profile. J Biol Chem 279:23229–23237. doi:10.1074/jbc.M400443200

    Article  CAS  PubMed  Google Scholar 

  11. Francois H, Facemire C, Kumar A et al (2007) Role of microsomal prostaglandin E synthase 1 in the kidney. J Am Soc Nephrol 18:1466–1475. doi:10.1681/ASN.2006040343

    Article  CAS  PubMed  Google Scholar 

  12. Chandrasekharan S, Foley NA, Jania L et al (2005) Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland. J Lipid Res 46:2636–2648. doi:10.1194/jlr.M500213-JLR200

    Article  CAS  PubMed  Google Scholar 

  13. Schneider A, Zhang Y, Zhang M et al (2004) Membrane-associated PGE synthase-1 (mPGES-1) is coexpressed with both COX-1 and COX-2 in the kidney. Kidney Int 65:1205–1213. doi:10.1111/j.1523-1755.2004.00493.x

    Article  CAS  PubMed  Google Scholar 

  14. Murakami M, Nakashima K, Kamei D et al (2003) Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2. J Biol Chem 278:37937–37947. doi:10.1074/jbc.M305108200

    Article  CAS  PubMed  Google Scholar 

  15. Han R, Smith TJ (2002) Cytoplasmic prostaglandin E2 synthase is dominantly expressed in cultured KAT-50 thyrocytes, cells that express constitutive prostaglandin-endoperoxide H synthase-2. Basis for low protaglandin E2 production. J Biol Chem 277:36897–36903. doi:10.1074/jbc.M206949200

    Article  CAS  PubMed  Google Scholar 

  16. Reid G, Wielinga P, Zelcer N et al (2003) The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci USA 100:9244–9249. doi:10.1073/pnas.1033060100

    Article  CAS  PubMed  Google Scholar 

  17. Rius M, Thon WF, Keppler D et al (2005) Prostanoid transport by multidrug resistance protein 4 (MRP4/ABCC4) localized in tissues of the human urogenital tract. J Urol 174:2409–2414. doi:10.1097/01.ju.0000180411.03808.cb

    Article  CAS  PubMed  Google Scholar 

  18. Bai J, Lai L, Yeo HC et al (2004) Multidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane-glutathione. Int J Biochem Cell Biol 36:247–257. doi:10.1016/S1357-2725(03)00236-X

    Article  CAS  PubMed  Google Scholar 

  19. Schuetz JD, Connelly MC, Sun D et al (1999) MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat Med 5:1048–1051. doi:10.1038/12487

    Article  CAS  PubMed  Google Scholar 

  20. Chen ZS, Lee K, Kruh GD (2001) Transport of cyclic nucleotides and estradiol 17-beta-D-glucuronide by multidrug resistance protein 4. Resistance to 6-mercaptopurine and 6-thioguanine. J Biol Chem 276:33747–33754. doi:10.1074/jbc.M104833200

    Article  CAS  PubMed  Google Scholar 

  21. Vandesompele J, De Preter K, Pattyn F et al (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3:research0034.1–0034.11

    Google Scholar 

  22. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45. doi:10.1093/nar/29.9.e45

    Article  CAS  PubMed  Google Scholar 

  23. Degousee N, Angoulvant D, Fazel S et al (2006) c-Jun N-terminal kinase-mediated stabilization of microsomal prostaglandin E2 synthase-1 mRNA regulates delayed microsomal prostaglandin E2 synthase-1 expression and prostaglandin E2 biosynthesis by cardiomyocytes. J Biol Chem 281:16443–16452. doi:10.1074/jbc.M602815200

    Article  CAS  PubMed  Google Scholar 

  24. Chandrasekharan NV, Simmons DL (2004) The cyclooxygenases. Genome Biol 5:241. doi:10.1186/gb-2004-5-9-241

    Article  CAS  PubMed  Google Scholar 

  25. Pebernard S, Iggo RD (2004) Determinants of interferon-stimulated gene induction by RNAi vectors. Differentiation 72:103–111. doi:10.1111/j.1432-0436.2004.07202001.x

    Article  CAS  PubMed  Google Scholar 

  26. Sledz CA, Holko M, de Veer MJ et al (2003) Activation of the interferon system by short-interfering RNAs. Nat Cell Biol 5:834–839. doi:10.1038/ncb1038

    Article  CAS  PubMed  Google Scholar 

  27. Smith WL, DeWitt DL, Garavito RM (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69:145–182. doi:10.1146/annurev.biochem.69.1.145

    Article  CAS  PubMed  Google Scholar 

  28. Samuelsson B, Morgenstern R, Jakobsson PJ (2007) Membrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol Rev 59:207–224. doi:10.1124/pr.59.3.1

    Article  CAS  PubMed  Google Scholar 

  29. Yang T (2007) Microsomal prostaglandin E synthase-1 and blood pressure regulation. Kidney Int 72:274–278. doi:10.1038/sj.ki.5002326

    Article  CAS  PubMed  Google Scholar 

  30. Ivanov AI, Romanovsky AA (2004) Prostaglandin E2 as a mediator of fever: synthesis and catabolism. Front Biosci 9:1977–1993. doi:10.2741/1383

    Article  CAS  PubMed  Google Scholar 

  31. Lin ZP, Zhu YL, Johnson DR et al (2008) Disruption of cAMP and prostaglandin E2 transport by multidrug resistance protein 4 deficiency alters cAMP-mediated signaling and nociceptive response. Mol Pharmacol 73:243–251. doi:10.1124/mol.107.039594

    Article  CAS  PubMed  Google Scholar 

  32. Zhou SF, Wang LL, Di YM et al (2008) Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. Curr Med Chem 15:1981–2039. doi:10.2174/092986708785132870

    Article  CAS  PubMed  Google Scholar 

  33. Kirtikara K, Morham SG, Raghow R et al (1998) Compensatory prostaglandin E2 biosynthesis in cyclooxygenase 1 or 2 null cells. J Exp Med 187:517–523. doi:10.1084/jem.187.4.517

    Article  CAS  PubMed  Google Scholar 

  34. Tanaka A, Hase S, Miyazawa T et al (2002) Up-regulation of cyclooxygenase-2 by inhibition of cyclooxygenase-1: a key to nonsteroidal anti-inflammatory drug-induced intestinal damage. J Pharmacol Exp Ther 300:754–761. doi:10.1124/jpet.300.3.754

    Article  CAS  PubMed  Google Scholar 

  35. Zhang J, Goorha S, Raghow R et al (2002) The tissue-specific, compensatory expression of cyclooxygenase-1 and -2 in transgenic mice. Prostaglandins Other Lipid Mediat 67:121–135. doi:10.1016/S0090-6980(01)00177-0

    Article  CAS  PubMed  Google Scholar 

  36. Gradilone A, Pulcinelli FM, Lotti LV et al (2007) Celecoxib induces MRP-4 in lung cancer cells: therapeutic implications. J Clin Oncol 25:4318–4320. doi:10.1200/JCO.2007.12.2945 Author reply 4320

    Article  PubMed  Google Scholar 

  37. Bock JM, Menon SG, Sinclair LL et al (2007) Celecoxib toxicity is cell cycle phase specific. Cancer Res 67:3801–3808. doi:10.1158/0008-5472.CAN-06-3780

    Article  CAS  PubMed  Google Scholar 

  38. Warner TD, Mitchell JA (2003) Nonsteroidal antiinflammatory drugs inhibiting prostanoid efflux: as easy as ABC? Proc Natl Acad Sci USA 100:9108–9110. doi:10.1073/pnas.1733826100

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

This study was supported by the grant NR8760-4/2006 from the Ministry of Health, Czech Republic and GENERI BIOTECH s.r.o.

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Authors and Affiliations

  1. GENERI BIOTECH s.r.o, Hradec Kralove, Czech Republic

    Hana Radilova, Antonin Libra, Sarka Holasova, Martina Safarova, Alena Viskova, Filip Kunc & Martin Buncek

  2. Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Prague, Czech Republic

    Hana Radilova

  3. Department of Medical Biology and Genetics, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Prague, Czech Republic

    Alena Viskova & Filip Kunc

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  1. Hana Radilova
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Correspondence to Hana Radilova.

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Radilova, H., Libra, A., Holasova, S. et al. COX-1 is coupled with mPGES-1 and ABCC4 in human cervix cancer cells. Mol Cell Biochem 330, 131–140 (2009). https://doi.org/10.1007/s11010-009-0126-1

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  • DOI: https://doi.org/10.1007/s11010-009-0126-1

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