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A critical role of integrin-linked kinase, ch-TOG and TACC3 in centrosome clustering in cancer cells

Oncogene volume 30, pages 521–534 (2011)Cite this article

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Abstract

Many cancer cells contain more than two centrosomes, which imposes a potential for multipolar mitoses, leading to cell death. To circumvent this, cancer cells develop mechanisms to cluster supernumerary centrosomes to form bipolar spindles, enabling successful mitosis. Disruption of centrosome clustering thus provides a selective means of killing supernumerary centrosome-harboring cancer cells. Although the mechanisms of centrosome clustering are poorly understood, recent genetic analyses have identified requirements for both actin and tubulin regulating proteins. In this study, we demonstrate that the integrin-linked kinase (ILK), a protein critically involved in actin and mitotic microtubule organization, is required for centrosome clustering. Inhibition of ILK expression or activity inhibits centrosome clustering in several breast and prostate cancer cell lines that have centrosome amplification. Furthermore, cancer cells with supernumerary centrosomes are significantly more sensitive to ILK inhibition than cells with two centrosomes, demonstrating that inhibiting ILK offers a selective means of targeting cancer cells. Live cell analysis shows ILK perturbation leads cancer cells to undergo multipolar anaphases, mitotic arrest and cell death in mitosis. We also show that ILK performs its centrosome clustering activity in a focal adhesion-independent, but centrosome-dependent, manner through the microtubule regulating proteins TACC3 and ch-TOG. In addition, we identify a specific TACC3 phosphorylation site that is required for centrosome clustering and demonstrate that ILK regulates this phosphorylation in an Aurora-A-dependent manner.

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Acknowledgements

This work was supported by grants to SD from the Canadian Institute of Health Research (CIHR) and the Canadian Cancer Society Research Institute, with funds raised by the Canadian Cancer Society. We thank Quadra Logic Technology Inc (QLT Inc), Vancouver, BC for supplying QLT-0267. We thank Dr Kazuhisa Kinoshita for the kind gift of anti-phospho-Ser558 TACC3 antibody and Dr Peter Lansdorp for the Aurora-A plasmid.

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Authors and Affiliations

  1. Department of Integrative Oncology, British Columbia Cancer Research Centre of the BC Cancer Agency, Vancouver, British Columbia, Canada

    A B Fielding, S Lim, K Montgomery, I Dobreva & S Dedhar

  2. Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada

    S Dedhar

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  1. A B Fielding
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  2. S Lim
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  3. K Montgomery
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Correspondence to S Dedhar.

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SD is a scientific consultant for Quadra Logic Technology Inc. (QLT Inc), Vancouver.

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Supplementary Information accompanies the paper on the Oncogene website

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Fielding, A., Lim, S., Montgomery, K. et al. A critical role of integrin-linked kinase, ch-TOG and TACC3 in centrosome clustering in cancer cells. Oncogene 30, 521–534 (2011). https://doi.org/10.1038/onc.2010.431

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