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

Oncogene. 2011 Feb 3;30(5):521-34. doi: 10.1038/onc.2010.431. Epub 2010 Sep 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinases
  • Azo Compounds / pharmacology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line
  • Cell Line, Tumor
  • Centrosome / metabolism*
  • Cytokinesis / drug effects
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Male
  • Microscopy, Fluorescence
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Phosphorylation
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein Binding
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pyrazoles / pharmacology
  • RNA Interference
  • Spindle Apparatus / drug effects
  • Spindle Apparatus / metabolism

Substances

  • Azo Compounds
  • CKAP5 protein, human
  • Microtubule-Associated Proteins
  • Pyrazoles
  • QLT 0267
  • TACC3 protein, human
  • integrin-linked kinase
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases