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.

  • Short Report
  • Published:

Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis

Oncogene volume 20, pages 6250–6257 (2001)Cite this article

Abstract

Mutation of the adenomatous polyposis coli (APC) gene and the subsequent dysregulation of β-catenin are well-documented abnormalities in familial adenomatous polyposis (FAP), as well as sporadic polyposis. Intriguingly, overexpression of the integrin-linked kinase (ILK) has been shown to modulate β-catenin subcellular localization and function. However, the significance of this finding for human carcinogenesis remains unclear. Here, we report the increased biochemical activity and expression of ILK protein in polyps from FAP patients. Furthermore, dramatic increases in ILK immunoreactivity were observed in all abnormal crypts from sporadic polyps, when compared with the normal appearing crypts within the same resected specimens. As sulindac and aspirin are the two most important therapeutic/chemopreventative agents demonstrated in colorectal carcinogenesis, in both humans and animals, further investigation revealed that these non-steroidal anti-inflammatory drugs (NSAIDs) target ILK and ILK-mediated events in vivo. These include inhibition of, both the biochemical activation of ILK, inhibition of serine 9 GSK3β phosphorylation and the enhancement of TCF-4 transcriptional activity. In conclusion, ILK protein hyperexpression appears to be an early event in colonic polyposis. Additionally, ILK signaling is shown to undergo modulation by sulindac (and aspirin) for the first time, indicating that it is likely to be one of the targets affected by these agents in vivo.

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

Similar content being viewed by others

References

  • Akashi H, Han HJ, Lizaka M, Nakamura Y . 2000 Int. J. Cancer 88: 873–880

  • Attwell S, Roskelley C, Dedhar S . 2000 Oncogene 19: 3811–3815

  • Barker N, Morin PJ, Clevers H . 2000 Adv. Cancer Res. 77: 1–24

  • Beazer-Barclay Y, Levy DB, Moser AR, Dove WF, Hamilton SR, Vogelstein B, Kinzler KW . 1996 Carcinogenesis 17: 1757–1760

  • Behrens J, Jerchow BA, Wurtele M, Grimm J, Asbrand C, Wirtz R, Kuhl M, Wedlich D, Birchmeier W . 1998 Science 280: 596–599

  • Chan TA, Morin PJ, Vogelstein B, Kinzler KW . 1998 Proc. Natl. Acad. Sci. 95: 681–686

  • Chiu CH, McEntee MF, Whelan J . 1997 Cancer Res. 57: 4267–4273

  • Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJ, Rubinfeld B, Polakis P, Matrisian LM . 1999 Oncogene 18: 2883–2891

  • D'Amico M, Hulit J, Amanatullah DF, Zafonte BT, Albanese C, Bouzahzah B, Fu MF, Augenlicht LH, Donehower LA, Takemaru KI, Moon RT, Davis R, Lisanti MP, Shtutman M, Zhurinsky J, Ben-Ze'ev A, Troussard AA, Dedhar S, Pestell RG . 2000 J. Biol. Chem. 275: 32649–32657

  • Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S . 1998 Proc. Natl. Acad. Sci. 95: 11211–11216

  • Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN . 1994 Gastroenterology 107: 1183–1188

  • Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Ruppert JM, Hamilton SR, Preisinger AC, Thomas G, Kinzler KW . 1990 Science 247: 49–46

  • Hanif R, Pittas A, Feng Y, Koutsos MI, Qiao L, Staiano-Coico L, Shiff SI, Rigas B . 1996 Biochem. Pharmaco. 52: 237–245

  • Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, Coppolino MG, Radeva G, Filmus J, Bell JC, Dedhar S . 1996 Nature 379: 91–96

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

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW . 1998 Science 281: 1509–1512

  • Hsu AL, Ching TT, Wang DS, Song XQ, Rangnekar VM, Chen CS . 2000 J. Biol. Chem. 275: 11397–11403

  • Iwamoto M, Ahnen DJ, Franklin WA, Maltzman TH . 2000 Carcinogenesis 21: 1935–1940

  • Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Presinger AC, Hedge P, McKechnie D . 1991 Science 253: 661–665

  • Korinek V, Barker N, Morin PJ, Vanwichen D, Deweger R, Kinzler KW, Vogelstein B, Clevers H . 1997 Science 275: 1784–1787

  • Labayle D, Fischer D, Vielh P, Drouhin F, Pariente A, Bories C, Duhamel O, Trousset M, Attali P . 1991 Gastroenterology 101: 635–639

  • Mann B, Gelos M, Siedow A, Hanski ML, Gratchev A, Ilyas M, Bodmer WF, Moyer MP, Riecken EO, Buhr HJ, Hanski C . 1999 Proc. Natl. Acad. Sci. 96: 1603–1608

  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW . 1997 Science 275: 1787–1790

  • Munstermann U, Fritz G, Seitz G, Lu YP, Schneider HR, Issinger OG . 1990 Eur. J. Biochem. 189: 251–257

  • Novak A, Hsu SC, Leung-Hagesteijn C, Radeva G, Papkoff J, Montesano R, Roskelley C, Grosschedl R, Dedhar S . 1998 Proc. Natl. Acad. Sci. 95: 4374–4379

  • O'Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, Scudiero DA, Monks A, Sausville EA, Weinstein JN, Friend S, Fornace Jr AJ, Kohn KW . 1997 Cancer Res. 57: 4285–4300

  • Perl AK, Wilgenbus P, Dahl U, Semb H, Christopfori G . 1998 Nature 392: 190–193

  • Persad S, Attwell S, Gray V, Delcommenne M, Troussard A, Sanghera J, Dedhar S . 2000 Proc. Natl. Acad. Sci. 97: 3207–3212

  • Piazza GA, Rahm AL, Krutzsch M, Sperl G, Paranka NS, Gross PH, Brendel K, Burt RW, Alberts DS, Pamukcu R . 1995 Cancer Res. 55: 3110–3116

  • Piazza GA, Alberts DS, Hixson LJ, Paranka NS, Li H, Finn T, Bogert C, Guillen JM, Brendel K, Gross PH, Sperl G, Ritchie J, Burt RW, Ellsworth L, Ahnen DJ, Pamukcu R . 1997 Cancer Res. 57: 2909–2915

  • Radeva G, Petrocelli T, Behrend E, Leung-Hagesteijn C, Filmus J, Slingerland J, Dedhar S . 1997 J. Biol. Chem. 272: 13937–13944

  • Reddy BS, Rao CV, Seibert K . 1996 Cancer Res. 56: 4566–4569

  • Rowan AJ, Lamlum H, Ilyas M, Wheeler J, Straub J, Papadopoulou A, Bicknell D, Bodmer WF, Tomlinson IP . 2000 Proc. Natl. Acad. Sci. 97: 3352–3357

  • Roose J, Huls G, van Beest M, Moerer P, van der Horn K, Goldschmeding R, Logtenberg T, Clevers H . 1999 Science 285: 1923–1926

  • Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P . 1996 Science 272: 1023–1026

  • Salh BS, Marotta A, Matthewson C, Ahluwalia M, Flint J, Owen D, Pelech S . 1999 Anticancer Res. 19: 731–740

  • Shiff SJ, Qiao L, Tsai LL, Rigas B . 1995 J. Clin. Invest. 96: 491–503

  • Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R, Ben-Ze'ev R . 1999 Proc. Natl. Acad. Sci. 96: 5522–5527

  • Sparks AB, Morin PJ, Vogestein B, Kinzler KW . 1998 Cancer Res. 58: 1130–1134

  • Tan C, Costello P, Sanghera J, Dominguez D, Baulida J, de Herreros AG, Dedhar S . 2001 Oncogene 20: 133–140

  • Troussard AA, Costello P, Yoganathan TN, Kumagai S, Roskelley C, Dedhar S . 2000 Oncogene 19: 5444–5452

  • Williams CS, Tsujii M, Reese J, Dey SK, DuBois RN . 2000 J. Clin. Invest. 105: 1589–1594

  • Wu C, Keightley SY, Leung-Hagesteijn C, Radeva G, Coppolino M, Goicoechea S, McDonald JA, Dedhar S . 1998 J. Biol. Chem. 273: 528–536

  • Yamamoto Y, Yin MJ, Lin KM, Gaynor RB . 1999 J. Biol. Chem. 274: 27307–27314

  • Zhang L, Yu J, Park BH, Kinzler KW, Vogelstein B . 2000 Science 290: 989–991

Download references

Acknowledgements

This work was supported by grants from the Cancer Research Society and the Northwestern Society for Intestinal Research to B Salh, and from the National Cancer Institute to S Dedhar. We thank Stressgen (Victoria, BC) for generously providing anti-ILK, anti-PKB, anti-GSK3 and anti-CK2 antibodies, and Dr H Clevers for the TOPFLASH and TOPFLASH constructs.

Author information

Authors and Affiliations

  1. Jack Bell Research Center, 2660 Oak Street, Vancouver, V6H 3Z6, BC, Canada

    Anthony Marotta, Clara Tan, Virginia Gray, Shoukat Dedhar & Baljinder Salh

  2. BC Cancer Agency, 600 W10th Ave, Vancouver, V5Z 4E6, BC, Canada

    Clara Tan, Virginia Gray & Shoukat Dedhar

  3. Thunderbay Regional Hospital, Thunderbay, P7E 1G6, ON, Canada

    Saleem Malik

  4. Mount Sinai Hospital, 600 University Ave, Toronto, M5G 1X5, ON, Canada

    Stephen Gallinger

  5. Kinetek Pharmaceuticals Inc., 1779 W75th Ave, Vancouver, V6P 6P2, BC, Canada

    Jasbinder Sanghera

  6. Vancouver General Hospital, 855 W12th Ave, Vancouver, V5Z 1M9, BC, Canada

    Beverely Dupuis & David Owen

Authors
  1. Anthony Marotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Clara Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Virginia Gray
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Saleem Malik
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen Gallinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jasbinder Sanghera
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Beverely Dupuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David Owen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shoukat Dedhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Baljinder Salh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Baljinder Salh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marotta, A., Tan, C., Gray, V. et al. Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis. Oncogene 20, 6250–6257 (2001). https://doi.org/10.1038/sj.onc.1204791

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204791

Keywords

This article is cited by

Search

Advanced search

Quick links