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The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9)

Oncogene volume 19, pages 5444–5452 (2000)Cite this article

Abstract

Overexpression of Integrin Linked Kinase (ILK) in intestinal and mammary epithelial cells results in a highly invasive phenotype, associated with increased levels of expression of the matrix metalloproteinase MMP-9. This increase was at the transcriptional level as determined by MMP-9 promoter-CAT reporter assays. Mutations in the two AP-1 binding sites within the MMP-9 promoter completely inhibited the reporter activity. We have previously shown that ILK inhibits glycogen synthase kinase-3 (GSK-3) activity. Transient transfection of wild-type GSK-3β in ILK-overexpressing cells decreased MMP-9 promoter activity and AP-1 activity, indicating that ILK can stimulate MMP-9 expression via GSK-3β and AP-1 transcription factor. A small molecule inhibitor of the ILK kinase reduced the in vitro invasiveness of ILK-overexpressing cells as well as the invasiveness of several human brain tumor cell lines. Furthermore, both MMP-9 promoter and AP-1 activities were inhibited by the ILK inhibitor. Invasiveness of ILK-overexpressing cells was also reduced by inhibition of MMP-9. These data demonstrate that ILK can induce an invasive phenotype via AP-1-dependent upregulation of MMP-9.

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Acknowledgements

We thank Gerry Krystal (British Columbia Cancer Agency, Canada) for constructing the MSCV-ILK-V5 vector, Douglas Boyd (University of Texas, USA) for the MMP-9 promoter plasmids, Christopher Overall (University of British Columbia, Canada) for the MMP inhibitor, and Warren McDonald and Rolando Del Maestro (Brain Research Laboratories, University of Western Ontario, Canada) for carrying out the brain tumor invasion assays. This work was supported by grants from the National Cancer Institute of Canada (NCIC) to S Dedhar and the Canadian Breast Cancer Research Initiative (CBCRI) to CD Roskelley.

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Authors and Affiliations

  1. BC Cancer Agency and Vancouver Hospital, Jack Bell Research Centre, 2660 Oak Street, Vancouver BC , V6H3Z6, Canada

    Armelle A Troussard & Shoukat Dedhar

  2. Kinetek Pharmaceuticals Inc., Vancouver BC, V6P6P2, Canada

    Penny Costello & T Nathan Yoganathan

  3. Kanazawa University, School of Medicine, Ishikawa 920, Japan

    Shigehiro Kumagai

  4. Department of Anatomy, University of British Columbia, Vancouver BC, V6T1Z3, Canada

    Calvin D Roskelley

  5. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver BC, V6T1Z3, Canada

    Shoukat Dedhar

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  1. Armelle A Troussard
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  2. Penny Costello
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  5. Calvin D Roskelley
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Troussard, A., Costello, P., Yoganathan, T. et al. The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9). Oncogene 19, 5444–5452 (2000). https://doi.org/10.1038/sj.onc.1203928

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