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 Paper
  • Published:

Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB/Akt activation, induces apoptosis, and delays tumor growth

Oncogene volume 24, pages 3596–3605 (2005)Cite this article

Abstract

The tumor suppressor gene phosphatase and tensin homologue (PTEN) regulates the phosphatidylinositol-3′-kinase (PI3K) signaling pathway and has been shown to correlate with poor prognosis in high-grade astrocytomas when mutational inactivation or loss of the PTEN gene occurs. PTEN mutation leads to constitutive activation of protein kinase B (PKB)/Akt with phosphorylation at the PKB/Akt sites Thr-308 and Ser-473. Integrin-linked kinase (ILK) has been shown to regulate PKB/Akt activity with the loss of PTEN in prostate cancer. We now demonstrate that ILK activity regulates PKB/Akt activity in glioblastoma cells. The activity of ILK is constitutively elevated in a serum-independent manner in PTEN mutant cells, and transfection of wild-type PTEN under the control of an inducible promoter into mutant PTEN cells inhibits ILK activity. Transfection of ILK antisense (ILKAS) or exposure to a small-molecule ILK inhibitor suppresses the constitutive phosphorylation of PKB/Akt on Ser-473 in PTEN-mutant glioblastoma cell lines. In addition, the delivery of ILKAS to PTEN-negative glioblastoma cells resulted in apoptosis. Rag-2M mice bearing established (∼100 mg) human U87MG glioblastoma tumors, treated QD × 5 for 3 consecutive weeks with ILKAS (i.p. 5 mg/kg), exhibited stable disease with ⩽7% increase in tumor volume over the 3-week course of treatment. In contrast, animals treated with an oligonucleotide control or saline exhibited a >100% increase in tumor volume over the same time period. Our initial results indicate that therapeutic strategies targeting ILK may be beneficial in the treatment of glioblastomas.

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
Figure 7

Similar content being viewed by others

Abbreviations

ILK:

integrin-linked kinase

PI3K:

phosphatidylinositol-3′-kinase

PTEN:

phosphatase and tensin homologue

MMAC1:

mutated in multiple advanced cancers

PI(3, 4, 5) P3:

phosphatidylinositol-3, 4, 5-triphosphate

DAPI:

4′,6-diamidino-2-phenylindole

CI:

combination index

GBM:

glioblastoma multiforme

ODN:

oligonucleotides

References

  • Cheney W, Neuteboom STC, Vaillancourt M-T, Ramachandra M and Bookstein R . (1999). Cancer Res., 59, 2318–2323.

  • Choe G, Horvath S, Cloughesy TF, Crosby K, Seligson D, Palotie A, Inge L, Smith BL, Sawyers CL and Mischel PS . (2003). Cancer Res., 63, 2742–2746.

  • Chung DH, Lee JI, Kook MC, Kim JR, Kim SH, Choi EY, Park SH and Song HG . (1998). Virchows Arch., 433, 113–117.

  • Cruet-Hennequart S, Maubant S, Luis J, Gauduchon P, Staedel C and Dedhar S . (2003). Oncogene, 22, 1688–1702.

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

  • Daumas-Duport C, Scheithauer BW, O'Fallon J and Kelly P . (1988). Cancer, 62, 2152–2165.

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

  • Edwards L, Thiessen B, Yan H, Dedhar S and Bally M . (2003). Neuro-Oncology, 5, 300 (abstract).

  • Edwards LA, Shabbits J, Bally MB and Dedhar S . (2004). Integrin-linked Kinase (ILK) in Combination Molecular Targeting: Cancer Treatment and Research. Kluwer: New York.

    Google Scholar 

  • Ermoian RP, Furniss CS, Lamborn KR, Basila D, Berger MS, Gottschalk AR, Nicholas MK, Stokoe D and Haas-Kogan DA . (2002). Clin. Cancer Res., 8, 1100–1106.

  • Graff JR, Deddens JA, Konicek BW, Colligan BM, Hurst BM, Carter HW and Carter JH . (2001). Clin. Cancer Res., 7, 1987–1991.

  • Haas-Koogan DA, Shaley N, Wong M, Mills G, Yount G and Stokoe D . (1998). Curr. Biol., 8, 1195–1198.

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

  • Hu Y, Cherton-Horvat G, Dragowska V, Baird S, Korneluk RG, Durkin JP, Mayer LD and LaCasse EC . (2003). Clin. Cancer Res., 9, 2826–2836.

  • Ishii T, Furuoka H, Muroi Y and Nishimura M . (2003). J. Biol. Chem., 278, 26970–26975.

  • Katso R, Okkenhaug K, Ahmadi K, White S, Timms J and Waterfield MD . (2001). Annu. Rev. Cell Dev. Biol., 17, 615–675.

  • Knobbe CB, Merlo A and Reifenberger G . (2002). Neuro-Oncology, 4, 196–211.

  • Li DM and Sun H . (1997). Cancer Res., 57, 2124–2129.

  • Li J, Yen C, Liaw D, Podyspaniana K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh B, Wigler MH and Parsons R . (1997). Science, 275, 1943–1947.

  • Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C and Parsons R . (1997). Nat. Genet., 16, 64–67.

  • Marsh DJ, Roth S, Lunetta KL, Hemminki A, Dahia PL, Sistonen P, Zheng Z, Caron S, van Orsouw NJ, Bodmer WF, Cottrell SE, Dunlop MG, Eccles D, Hodgson SV, Jarvinen H, Kellokumpu I, Markie D, Neale K, Phillips R, Rozen P, Syngal S, Vijg J, Tomlinson IP, Aaltonen LA and Eng C . (1997). Cancer Res., 57, 5017–5021.

  • Nelen MR, van Staveren WC, Peeters EA, Hassel MB, Gorlin RJ, Hamm H, Lindboe CF, Fryns JP, Sijmons RH, Woods DG, Mariman EC, Padberg GW and Kremer H . (1997). Hum. Mol. Genet., 6, 1383–1387.

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

  • Obara S, Nakata M, Takeshima H, Katagiri H, Asano T, Oka Y, Maryuma I and Kuratsu J . (2004). Can. Lett., 208, 115–122.

  • Park M-J, Kim M-S, Park I-C, Kang H-S, Yoo H, Park S-H, Rhee CH, Hong S-I and Lee S-H . (2002). Can. Res., 62, 6318–6322.

  • Persad S, Attwell S, Gray V, Delecommenne M, Troussard A, Sanghera J and Dedhar S . (2000). Proc. Natl. Acad. Sci. USA, 97, 1322–1324.

  • Persad S, Attwell S, Gray V, Mawji N, Deng JT, Leung D, Yan J, Sanghera J, Walsh MP and Dedhar S . (2001). J. Biol. Chem., 276, 27462–27469.

  • Pore N, Liu S, Haas-Kogan DA, O'Rourke DM and Maity A . (2003). Cancer Res., 63, 236–241.

  • Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penniger JM, Siderovski DP and Mak TW . (1998). Cell, 95, 29–39.

  • Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Thaylon D, Frye C, Hu R, Swedlund B, Teng DHR and Tavtigian SV . (1997). Nat. Genet., 15, 356–362.

  • Stolarov J, Chang K, Reiner A, Rodgers L, Hannon GJ, Wigler MH and Mittal V . (2001). Proc. Natl. Acad. Sci. USA, 98, 13043–13048.

  • Tan C, Cruet-Hennequart S, Troussard A, Fazli L, Costello P, Sutton K, Wheeler J, Gleave M, Sanghera J and Dedhar S . (2004). Cancer Cell., 5, 79–90.

  • Tan C, Mui A and Dedhar S . (2002). J. Biol. Chem., 277, 3109–3116.

  • Troussard AA, Costello P, Yoganathan TN, Kumagai S, Roskelley CD and Dedhar S . (2000). Oncogene, 19, 5444–5452.

  • Tsou HC, Teng DH, Ping XL, Brancolini V, Davis T, Hu R, Xie XX, Gruener AC, Schrager CA, Christiano AM, Eng C, Steck P, Ott J, Tavtigian SV and Peacocke M . (1997). Am. J. Hum. Genet., 61, 1036–1043.

  • Tu Y, Li F and Wu C . (1998). Mol. Biol. Cell, 9, 3367–3382.

  • Wang SI, Puc J, Li J, Bruce JN, Cairns P and Sidransky D . (1997). Cancer Res., 57, 4183–4186.

  • Waterhouse DN, Dragowska WH, Gelmon KA, Mayer LD and Bally MB . (2004). Can. Biol. Ther., 3, 197–204.

  • White DE, Cardiff RD, Dedhar S and Muller WJ . (2001). Oncogene, 20, 7064–7072.

Download references

Acknowledgements

We thank Dr Mike Wigler and Linda Rogers at Cold Spring Harbour for their generous contribution of the U87 cells with the vector constructs. The Animal Technicians of Advanced Therapeutics for maintaining the mice, and QLT Inc./Kinetek Pharmaceuticals for the small-molecule ILK inhibitor. This research was funded by the NCIC Terry Fox New Frontiers Initiative.

Author information

Authors and Affiliations

  1. Department of Advanced Therapeutics, BC Cancer Agency, Vancouver, BC, Canada

    Lincoln A Edwards, Wieslawa H Dragowska & Marcel B Bally

  2. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

    Lincoln A Edwards, B Thiessen & Marcel B Bally

  3. Department of Medical Oncology, BC Cancer Agency, Vancouver, BC, Canada

    B Thiessen & Marcel B Bally

  4. Department of Medicinal Chemistry, QLT Inc, Vancouver, BC, Canada

    Tim Daynard

  5. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

    Marcel B Bally

  6. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada

    Shoukat Dedhar

  7. Department of Cancer Genetics, BC Cancer Agency, Vancouver, BC, Canada

    Shoukat Dedhar

Authors
  1. Lincoln A Edwards
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B Thiessen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wieslawa H Dragowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tim Daynard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marcel B Bally
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shoukat Dedhar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lincoln A Edwards.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Edwards, L., Thiessen, B., Dragowska, W. et al. Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB/Akt activation, induces apoptosis, and delays tumor growth. Oncogene 24, 3596–3605 (2005). https://doi.org/10.1038/sj.onc.1208427

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208427

Keywords

This article is cited by

Search

Advanced search

Quick links