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Inhibition of integrin linked kinase (ILK) suppresses β-catenin-Lef/Tcf-dependent transcription and expression of the E-cadherin repressor, snail, in APC−/− human colon carcinoma cells

Oncogene volume 20, pages 133–140 (2001)Cite this article

Abstract

Loss of functional adenomatous polyposis coli (APC) protein results in the stabilization of cytosolic β-catenin and activation of genes that are responsive to Lef/Tcf family transcription factors. We have recently shown that an independent cell adhesion and integrin linked kinase (ILK)-dependent pathway can also activate β-catenin/LEF mediated gene transcription and downregulate E-cadherin expression. In addition, ILK activity and expression are elevated in adenomatous polyposis and colon carcinomas. To examine the role of this pathway in the background of APC mutations we inhibited ILK activity in APC−/− human colon carcinoma cell lines. In all cases, inhibition of ILK resulted in substantial inhibition of TCF mediated gene transcription and inhibition of transcription and expression of the TCF regulated gene, cyclin D1. Inhibition of ILK resulted in decreased nuclear beta-catenin expression, and in the inhibition of phosphorylation of GSK-3 and stimulation of its activity, leading to accelerated degradation of β-catenin. In addition, inhibition of ILK suppressed cell growth in culture as well as growth of human colon carcinoma cells in SCID mice. Strikingly, inhibition of ILK also resulted in the transcriptional stimulation of E-cadherin expression and correlated with the inhibition of gene transcription of snail, a repressor of E-cadherin gene expression. Overexpression of ILK caused a stimulation of expression of snail, but snail expression was found not to be regulated by β-catenin/Tcf. These data demonstrate that ILK can regulate β-catenin/TCF and snail transcription factors by distinct pathways. We propose that inhibition of ILK may be a useful strategy in the control of progression of colon as well as other carcinomas.

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Acknowledgements

This work was supported by grants to S Dedhar from the National Cancer Institute of Canada and from La Marató de TV3 to A Garcia de Herreros. D Dominguez is a recipient of an Instituto de Salud Carlos III fellowship. We thank Rachel Madsen for preparing the manuscript and Dr Jim Woodgett for valuable discussions. The pTOPFlash and the pFOPFlash constructs were kindly provided by Dr Hans Clevers (University Hospital, Utrecht). The Cyclin D1 promoter construct was kindly provided by Dr Tetsu (University of California, San Francisco).

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Authors and Affiliations

  1. BC Cancer Agency and Jack Bell Research Centre, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada

    Clara Tan & Shoukat Dedhar

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

    Clara Tan, Penny Costello & Shoukat Dedhar

  3. Kinetek Pharmaceuticals Inc., Vancouver, BC V6P 6P2, Canada

    Jasbinder Sanghera

  4. Unitat de Biologia Cellular I Molecular, Institut Municipal d'Investigació Medica, Universitat Pompeu Fabra, Barcelona, Spain

    David Dominguez, Josep Baulida & Antonio Garcia de Herreros

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  1. Clara Tan
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Tan, C., Costello, P., Sanghera, J. et al. Inhibition of integrin linked kinase (ILK) suppresses β-catenin-Lef/Tcf-dependent transcription and expression of the E-cadherin repressor, snail, in APC−/− human colon carcinoma cells. Oncogene 20, 133–140 (2001). https://doi.org/10.1038/sj.onc.1204052

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