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:

Effect of aspirin on the Wnt/β-catenin pathway is mediated via protein phosphatase 2A

Oncogene volume 25, pages 6447–6456 (2006)Cite this article

Abstract

Nonsteroidal anti-inflammatory drugs show chemopreventive efficacy in colon cancer, but the mechanism behind this remains unclear. Elucidating this mechanism is seen as vital to the development of new chemopreventive agents. We studied the effects of aspirin on the oncogenic Wnt/β-catenin pathway activity in colorectal cancer cell lines and observed that aspirin dose-dependently decreased the activity of this pathway, as judged by TCF-driven luciferase activity, reduced Wnt target gene expression and increased phosphorylation of β-catenin by immunoblotting. Furthermore, the ubiquitination and cytoplasmic levels of β-catenin were assessed by immunoblotting, and also the localization of β-catenin was shown by green fluorescent protein-tagged β-catenin and time-lapse fluorescent imaging. Importantly, aspirin treatment caused increased phosphorylation of protein phosphatase 2A (PP2A), an event associated with inhibition of PP2A enzymatic activity, which was confirmed by a reduction in enzymatic PP2A activity. Moreover, this inhibition of PP2A enzymatic activity was essential for the effects of aspirin on the Wnt/β-catenin pathway as shown by transient transfection with PP2A constructs. The findings in this article provide a molecular explanation for the efficacy of aspirin in chemoprevention of colorectal cancer and shows biochemical evidence that PP2A is an important regulator of Wnt/β-catenin pathway activity in these cells.

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

  • Baek SJ, Kim KS, Nixon JB, Wilson LC, Eling TE . (2001). Mol Pharmacol 59: 901–908.

  • Boon EM, van der Neut R, van de Wetering M, Clevers H, Pals ST . (2002). Cancer Res 62: 5126–5128.

  • Charalambous D, O'Brien PE . (1996). J Gastroenterol Hepatol 11: 307–310.

  • Chung H, Nairn AC, Murata K, Brautigan DL . (1999). Biochemistry 38: 10371–10376.

  • Dihlmann S, Klein S, von Knebel Doeberitz M . (2003). Mol Cancer Ther 2: 509–516.

  • Dihlmann S, Siermann A, von Knebel Doeberitz M . (2001). Oncogene 20: 645–653.

  • Favre B, Turowski P, Hemmings BA . (1997). J Biol Chem 272: 13856–13863.

  • Giovannucci E, Egan KM, Hunter DJ, Stampfer MJ, Colditz GA, Willett WC et al. (1995). N Engl J Med 333: 609–614.

  • Green DW, Roh H, Pippin JA, Drebin JA . (2001). J Surg Res 101: 16–20.

  • Gupta RA, DuBois RN . (1998). Gastroenterology 114: 1095–1098.

  • Hanif R, Pittas A, Feng Y, Koutsos MI, Qiao L, Staiano-Coico L et al. (1996). Biochem Pharmacol 52: 237–245.

  • He TC, Chan TA, Vogelstein B, Kinzler KW . (1999). Cell 99: 335–345.

  • Husain SS, Szabo IL, Tamawski AS . (2002). Am J Gastroenterol 97: 542–553.

  • Kishimoto Y, Takata N, Jinnai T, Morisawa T, Shiota G, Kawasaki H et al. (2000). Gut 47: 812–819.

  • Kitagawa M, Hatakeyama S, Shirane M, Matsumoto M, Ishida N, Hattori K et al. (1999). EMBO J 18: 2401–2410.

  • Kopp E, Ghosh S . (1994). Science 265: 956–959.

  • Labayle D, Fischer D, Vielh P, Drouhin F, Pariente A, Bories C et al. (1991). Gastroenterology 101: 635–639.

  • Mann B, Gelos M, Siedow A, Hanski ML, Gratchev A, Ilyas M et al. (1999). Proc Natl Acad Sci USA 96: 1603–1608.

  • Marx J . (2001). Science 291: 581–582.

  • Miller JR, Hocking AM, Brown JD, Moon RT . (1999). Oncogene 18: 7860–7872.

  • Mistry SJ, Li HC, Atweh GF . (1998). Biochem J 334 (Part 1): 23–29.

  • Morin PJ . (1999). Bioessays 21: 1021–1030.

  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B et al. (1997). Science 275: 1787–1790.

  • Munemitsu S, Albert I, Souza B, Rubinfeld B, Polakis P . (1995). Proc Natl Acad Sci USA 92: 3046–3050.

  • Nunbhakdi-Craig V, Machleidt T, Ogris E, Bellotto D, White III CL, Sontag E . (2002). J Cell Biol 158: 967–978.

  • Orena SJ, Torchia AJ, Garofalo RS . (2000). J Biol Chem 275: 15765–15772.

  • Orford K, Crockett C, Jensen JP, Weissman AM, Byers SW . (1997). J Biol Chem 272: 24735–24738.

  • Oshima H, Oshima M, Kobayashi M, Tsutsumi M, Taketo MM . (1997). Cancer Res 57: 1644–1649.

  • Polakis P . (1997). Biochim Biophys Acta 1332: F127–F147.

  • Ratcliffe MJ, Itoh K, Sokol SY . (2000). J Biol Chem 275: 35680–35683.

  • Roh H, Green DW, Boswell CB, Pippin JA, Drebin JA . (2001). Cancer Res 61: 6563–6568.

  • Schonthal AH . (2001). Cancer Lett 170: 1–13.

  • Seeling JM, Miller JR, Gil R, Moon RT, White R, Virshup DM . (1999). Science 283: 2089–2091.

  • Seidensticker MJ, Behrens J . (2000). Biochim Biophys Acta 1495: 168–182.

  • Smal C, Cardoen S, Bertrand L, Delacauw A, Ferrant A, Van den Berghe G et al. (2004). Biochem Pharmacol 68: 95–103.

  • Smith ML, Hawcroft G, Hull MA . (2000). Eur J Cancer 36: 664–674.

  • Stark LA, Din FV, Zwacka RM, Dunlop MG . (2001). FASEB J 15: 1273–1275.

  • Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB et al. (2000). N Engl J Med 342: 1946–1952.

  • Tegeder I, Pfeilschifter J, Geisslinger G . (2001). FASEB J 15: 2057–2072.

  • Thun MJ, Namboodiri MM, Heath Jr CW . (1991). N Engl J Med 325: 1593–1596.

  • van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J et al. (1997). Cell 88: 789–799.

  • Xie H, Litersky JM, Hartigan JA, Jope RS, Johnson GV . (1998). Brain Res 798: 173–183.

Download references

Author information

Authors and Affiliations

  1. Laboratory of Experimental Oncology and Radiobiology, University of Amsterdam, The Netherlands

    C L Bos

  2. Department of Oncology, University of Amsterdam, The Netherlands

    C L Bos & D J Richel

  3. Laboratory of Experimental Internal Medicine, University of Amsterdam, The Netherlands

    L L Kodach & M M van Santen

  4. Department of Gastroenterology, University of Amsterdam, The Netherlands

    G R van den Brink & J C H Hardwick

  5. Department of Cell Biology, University of Groningen, The Netherlands

    S H Diks & M P Peppelenbosch

Authors
  1. C L Bos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L L Kodach
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G R van den Brink
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S H Diks
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M M van Santen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D J Richel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M P Peppelenbosch
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J C H Hardwick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J C H Hardwick.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bos, C., Kodach, L., van den Brink, G. et al. Effect of aspirin on the Wnt/β-catenin pathway is mediated via protein phosphatase 2A. Oncogene 25, 6447–6456 (2006). https://doi.org/10.1038/sj.onc.1209658

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209658

Keywords

This article is cited by

Search

Advanced search

Quick links