Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

Oncogene volume 31, pages 2943–2952 (2012)Cite this article

Abstract

Accumulating evidence indicates that cyclooxygenase (COX)-2-derived prostaglandin (PG) E2 is involved in the development of various tumors, including colorectal cancer. However, the precise contribution of microsomal PGE synthase (mPGES)-1, a terminal enzyme that acts downstream of COX-2 in the PGE2-biosynthetic pathway, to multiple processes of tumor development is not yet fully understood. Here, we show the pro-tumorigenic role of mPGES-1 in chemical carcinogen-induced colon carcinogenesis and intrasplenic tumor transplantation models. Genetic deletion of mPGES-1 significantly reduced both the total number and size of colorectal polyps at 18 weeks after azoxymethane administration with reduced nuclear translocation of β-catenin, altered expression profiles of chemokines/cytokines and increased production of antitumorigenic PGs, prostaglandin D2 and prostacyclin in tumor tissues. At an early stage (6 weeks), mPGES-1 deficiency significantly reduced the number of aberrant crypt foci, while its transgenic overexpression increased the number. Furthermore, the growth of intrasplenically transplanted tumor cells was suppressed in mPGES-1 knockout (KO) mice. Co-culture of tumor cells with bone marrow-derived macrophages (BM-MΦs) isolated from wild-type (WT) mice resulted in the induction of mPGES-1 in BM-MΦs and increased the growth of tumor cells in vitro, whereas mPGES-1-null BM-MΦs failed to facilitate tumor growth. The adoptive transfer of WT BM-MΦs into mPGES-1 KO mice restored the growth of transplanted tumor cells, indicating that mPGES-1 in MΦs is important for the growth of adjacent tumor cells. Taken together, our findings suggest that the inhibition of mPGES-1 is an alternative therapeutic target for colorectal and possibly other cancers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Ban JO, Kwak DH, Oh JH, Park EJ, Cho MC, Song HS et al. (2010). Suppression of NF-κB and GSK-3β is involved in colon cancer cell growth inhibition by the PPAR agonist troglitazone. Chem Biol Interact 188: 75–85.

    Article  CAS  PubMed  Google Scholar 

  • Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B et al. (2000). Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 343: 1520–1528.

    Article  CAS  PubMed  Google Scholar 

  • Boulet L, Ouellet M, Bateman KP, Ethier D, Percival MD, Riendeau D, Mancini JA 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.

    Article  CAS  PubMed  Google Scholar 

  • Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K et al. (2005). Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352: 1092–1102.

    Article  CAS  PubMed  Google Scholar 

  • Casós K, Siguero L, Fernández-Figueras MT, León X, Sardá MP, Vila L et al. (2011). Tumor cells induce COX-2 and mPGES-1 expression in microvascular endothelial cells mainly by means of IL-1 receptor activation. Microvasc Res 81: 261–268.

    Article  PubMed  Google Scholar 

  • Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS . (2005). Prostaglandin E2 promotes colon cancer cell growth through a Gs–axin–β-catenin signaling axis. Science 310: 1504–1510.

    Article  CAS  PubMed  Google Scholar 

  • Cathcart MC, Reynolds JV, O'Byrne KJ, Pidgeon GP . (2010). The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer. Biochim Biophys Acta 1805: 153–166.

    CAS  PubMed  Google Scholar 

  • Garg A, Aggarwal BB . (2002). Nuclear transcription factor-κB as a target for cancer drug development. Leukemia 16: 1053–1068.

    Article  CAS  PubMed  Google Scholar 

  • Golijanin D, Tan JY, Kazior A, Cohen EG, Russo P, Dalbagni G et al. (2004). Cyclooxygenase-2 and microsomal prostaglandin E synthase-1 are overexpressed in squamous cell carcinoma of the penis. Clin Cancer Res 10: 1024–1031.

    Article  CAS  PubMed  Google Scholar 

  • Guda K, Upender MB, Belinsky G, Flynn C, Nakanishi M, Marino JN et al. (2004). Carcinogen-induced colon tumors in mice are chromosomally stable and are characterized by low-level microsatellite instability. Oncogene 23: 3813–3821.

    Article  CAS  PubMed  Google Scholar 

  • Hanaka H, Pawelzik S-C, Johnsen JI, Rakonjac M, Terawaki K, Rasmuson A et al. (2009). Microsomal prostaglandin E synthase 1 determines tumor growth in vivo of prostate and lung cancer cells. Proc Natl Acad Sci USA 44: 18757–18762.

    Article  Google Scholar 

  • Hara S, Kamei D, Sasaki Y, Tanemoto A, Nakatani Y, Murakami M . (2010). Prostaglandin E synthases: understanding their pathophysiologial roles through mouse genetic models. Biochimie 92: 651–659.

    Article  CAS  PubMed  Google Scholar 

  • Hembruff SL, Cheng N . (2009). Chemokine signaling in cancer: implications on the tumor microenvironment and therapeutic targeting. Cancer Ther 7: 254–267.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jakobsson PJ, Thoren S, Morgenstern R, Samuelsson B . (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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jemal A, Siegel R, Xu J, Ward E . (2010). Cancer statistics, 2010. CA Cancer J Clin 60: 277–300.

    Article  PubMed  Google Scholar 

  • Kamata H, Hosono K, Suzuki T, Ogawa Y, Kubo H, Katoh H et al. (2010). mPGES-1-expressing bone marrow-derived cells enhance tumor growth and angiogenesis in mice. Biomed Pharmacother 64: 409–416.

    Article  CAS  PubMed  Google Scholar 

  • Kamei D, Murakami M, Nakatani Y, Ishikawa Y, Ishii T, Kudo I . (2003). Potential role of microsomal prostaglandin E synthase-1 in tumorigenesis. J Biol Chem 278: 19396–19405.

    Article  CAS  PubMed  Google Scholar 

  • Kamei D, Murakami M, Sasaki Y, Nakatani Y, Majima M, Ishikawa Y et al. (2010). Microsomal prostaglandin E synthase-1 in both cancer cells and hosts contributes to tumour growth, invasion and metastasis. Biochem J 425: 361–371.

    Article  CAS  Google Scholar 

  • Kamei D, Yamakawa K, Takegoshi Y, Mikami-Nakanishi M, Nakatani Y, Oh-Ishi S et al. (2004). Reduced pain hypersensitivity and inflammation in mice lacking microsomal prostaglandin E synthase-1. J Biol Chem 279: 33684–33695.

    Article  CAS  PubMed  Google Scholar 

  • Kanegae Y, Takamori K, Sato Y, Lee G, Nakai M, Saito I . (1996). Efficient gene activation system on mammalian cell chromosomes using recombinant adenovirus producing Cre recombinase. Gene 181: 207–2012.

    Article  CAS  PubMed  Google Scholar 

  • Keith RL, Miller YE, Hudish TM, Girod CE, Sotto-Santiago S, Franklin WA et al. (2004). Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice. Cancer Res 64: 5897–5904.

    Article  CAS  PubMed  Google Scholar 

  • Lavergne E, Combadière C, Iga M, Boissonnas A, Bonduelle O, Maho M et al. (2004). Intratumoral CC chemokine ligand 5 overexpression delays tumor growth and increases tumor cell infiltration. J Immunol 173: 3755–3762.

    Article  CAS  PubMed  Google Scholar 

  • Mancini JA, Blood K, Guay J, Gordon R, Claveau D, Chan CC et al. (2001). Cloning, expression, and up-regulation of inducible rat prostaglandin e synthase during lipopolysaccharide-induced pyresis and adjuvant-induced arthritis. J Biol Chem 276: 4469–4475.

    Article  CAS  PubMed  Google Scholar 

  • Mansure JJ, Nassim R, Kassouf W . (2009). Peroxisome proliferator-activated receptor γ in bladder cancer: a promising therapeutic target. Cancer Biol Ther 8: 1–9.

    Article  Google Scholar 

  • Murakami M, Kudo I . (2004). Recent advances in molecular biology and physiology of the prostaglandin E2-biosynthetic pathway. Prog Lipid Res 43: 3–35.

    Article  CAS  PubMed  Google Scholar 

  • Murakami M, Naraba H, Tanioka T, Semmyo N, Nakatani Y, Kojima F 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.

    Article  CAS  PubMed  Google Scholar 

  • Nakanishi M, Menoret A, Tanaka T, Miyamoto S, Montrose DC, Vella AT et al. (2011). Selective PGE2 suppression impairs colon carcinogenesis and modifies local mucosal immunity. Cancer Prevent Res 4: 1198–1208.

    Article  CAS  Google Scholar 

  • Nakanishi M, Montrose DC, Clark P, Nambiar PR, Belinsky GS, Claffey KP et al. (2008). Genetic deletion of mPGES-1 suppresses intestinal tumorigenesis. Cancer Res 68: 3251–3259.

    Article  CAS  PubMed  Google Scholar 

  • Nakatani Y . (2007). Regulation of cytosolic prostaglandin E synthase. J Health Sci 53: 251–256.

    Article  CAS  Google Scholar 

  • Nambiar PR, Girnun G, Lillo NA, Guda K, Whiteley HE, Rosenberg DW . (2003). Preliminary analysis of azoxymethane induced colon tumors in inbred mice commonly used as transgenic/knockout progenitors. Int J Oncol 22: 145–150.

    CAS  PubMed  Google Scholar 

  • Osawa E, Nakajima A, Wada K, Ishimine S, Fujisawa N, Kawamori T et al. (2003). Peroxisome proliferator-activated receptor γ ligands suppress colon carcinogenesis induced by azoxymethane in mice. Gastroenterology 124: 361–367.

    Article  CAS  PubMed  Google Scholar 

  • Oshima H, Oshima M, Inaba K, Taketo MM . (2004). Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice. EMBO J 23: 1669–1678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oshima M, Oshima H, Matsunaga A, Taketo MM . (2005). Hyperplastic gastric tumors with spasmolytic polypeptide-expressing metaplasia caused by tumor necrosis factor-alpha-dependent inflammation in cyclooxygenase-2/microsomal prostaglandin E synthase-1 transgenic mice. Cancer Res 65: 9147–9151.

    Article  CAS  PubMed  Google Scholar 

  • Ohtsuki M, Taketomi T, Arata S, Masuda S, Ishikawa T, Ishii T et al. (2006). Transgenic expression of group V, but not group X, secreted phospholipase A2 in mice leads to neonatal lethality because of lung dysfunction. J Biol Chem 281: 36420–36433.

    Article  CAS  PubMed  Google Scholar 

  • Park JM, Kanaoka Y, Eguchi N, Aritake K, Grujic S, Materi AM et al. (2007). Hematopoietic prostaglandin D synthase suppresses intestinal adenomas in ApcMin/+ mice. Cancer Res 67: 881–889.

    Article  CAS  PubMed  Google Scholar 

  • Qian X, Zhang J, Liu J . (2011). Tumor-secreted PGE2 inhibits CCL5 production in activated macrophages through cAMP/PKA signaling pathway. J Biol Chem 286: 2111–2120.

    Article  CAS  PubMed  Google Scholar 

  • Robinson SC, Scott KA, Wilson JL, Thompson RG, Proundfoot AE, Balkwill FR . (2003). A chemokine receptor antagonist inhibits experimental breast tumor growth. Cancer Res 63: 8360–8365.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Scher JU, Pillinger MH . (2005). 15d-PGJ2: the anti-inflammatory prostaglandin? Clin Immunol 114: 100–109.

    Article  CAS  PubMed  Google Scholar 

  • Segditsas S, Tomlinson I . (2006). Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 25: 7531–7537.

    Article  CAS  PubMed  Google Scholar 

  • Singh B, Vincent L, Berry JA, Multani AS, Lucci A . (2007). Cyclooxygenase-2 expression induces genomic instability in MCF10A breast epithelial cells. J Surg Res 140: 220–226.

    Article  CAS  PubMed  Google Scholar 

  • Stichtenoth DO, Thoren S, Bian H, Peters-Golden M, Jakobsson PJ, Crofford LJ . (2001). Microsomal prostaglandin E synthase is regulated by proinflammatory cytokines and glucocorticoids in primary rheumatoid synovial cells. J Immunol 167: 469–474.

    Article  CAS  PubMed  Google Scholar 

  • Thompson EA . (2007). PPARγ physiology and pathology in gastrointestinal epithelial cells. Mol Cells 24: 167–176.

    CAS  PubMed  Google Scholar 

  • Tsujii M, DuBois RN . (1995). Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 83: 493–501.

    Article  CAS  PubMed  Google Scholar 

  • Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN . (1998). Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93: 705–716.

    Article  CAS  PubMed  Google Scholar 

  • Wang D, DuBois RN . (2010a). The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene 29: 781–788.

    Article  CAS  PubMed  Google Scholar 

  • Wang D, DuBois RN . (2010b). Eicosanoids and cancer. Nat Rev Cancer 10: 181–193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research; by a Private University High Technology Research Center Project matching-fund subsidy from the Ministry of Education, Sports, Science, Culture and Technology of Japan; and by a Showa University Special Grant-in-Aid for Innovative Collaborative Research Projects. D Kamei was supported by Research Fellowships from the Japan Society for the Promotion of Science for Young Scientists. M Murakami was supported by PRESTO from the Japan Science and Technology Agency.

Author information

Authors and Affiliations

  1. Department of Health Chemistry, School of Pharmacy, Showa University, Tokyo, Japan

    Y Sasaki, D Kamei, M Murakami & S Hara

  2. Department of Research and Development for Innovative Medical Needs, School of Pharmacy, Showa University, Tokyo, Japan

    D Kamei

  3. Department of Pathology, School of Medicine, Toho University, Tokyo, Japan

    Y Ishikawa & T Ishii

  4. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

    S Uematsu & S Akira

  5. Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    M Murakami

Authors
  1. Y Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Kamei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Ishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Ishii
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Uematsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Akira
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Hara.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sasaki, Y., Kamei, D., Ishikawa, Y. et al. Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis. Oncogene 31, 2943–2952 (2012). https://doi.org/10.1038/onc.2011.472

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.472

Keywords

This article is cited by

Search

Advanced search

Quick links