Inhibition of CPAP–tubulin interaction prevents proliferation of centrosome‐amplified cancer cells

• Aruljothi Mariappan ^[1] ; Komal Soni ^[7] ; Kenji Schorpp ^[8] ; Fan Zhao ^[9] ; Amin Minakar ^[2] ; Xiangdong Zheng ^[9] ; Sunit Mandad ^[3] ; Iris Macheleidt ^[10] ; Anand Ramani ^[11] ; Tomáš Kubelka ^[4] ; Maciej Dawidowski ^[12] ; Kristina Golfmann ^[2] ; Arpit Wason ^[2] ; Chunhua Yang ^[5] ; Judith Simons ^[2] ; Hans‐Günther Schmalz ^[2] ; Anthony A Hyman ^[6] ; Ritu Aneja ^[5] ; Roland Ullrich ^[2] ; Henning Urlaub ^[3] ; Margarete Odenthal ^[10] ; Reinhardt Büttner ^[10] ; Haitao Li ^[9] ; Michael Sattler ^[7] ; Kamyar Hadian ^[8] ; Jay Gopalakrishnan ^[1]
  1. [1] Düsseldorf University Hospital

     Düsseldorf University Hospital

     Kreisfreie Stadt Düsseldorf, Alemania

     
  2. [2] University of Cologne

     University of Cologne

     Kreisfreie Stadt Köln, Alemania

     
  3. [3] Max Planck Institute for Biophysical Chemistry

     Max Planck Institute for Biophysical Chemistry

     Landkreis Göttingen, Alemania

     
  4. [4] Technical University Munich

     Technical University Munich

     Kreisfreie Stadt München, Alemania

     
  5. [5] Georgia State University

     Georgia State University

     Estados Unidos

     
  6. [6] Max Planck Institute of Molecular Cell Biology and Genetics

     Max Planck Institute of Molecular Cell Biology and Genetics

     Kreisfreie Stadt Dresden, Alemania

     
  7. [7] 3 Institute of Structural Biology Helmholtz Zentrum München Neuherberg Germany; 4 Biomolecular NMR at Center for Integrated Protein Science Munich and Department Chemie Technische Universität München Garching Germany
  8. [8] 5 Assay Development and Screening Platform Institute of molecular Toxicology and Pharmacology Helmholtz Zentrum München—German Research Center for Environmental Health Neuherberg Germany
  9. [9] 6 Department of Basic Medical Sciences Center for Structural Biology School of Medicine Beijing China; 7 MOE Key Laboratory of Protein Sciences School of Life Sciences Beijing China; 8 Tsinghua‐Peking Center for Life Sciences Tsinghua University Beijing China
  10. [10] 13 Institute of Pathology and Center for Molecular Medicine of the University of Cologne Cologne Germany
  11. [11] 1 Institute für Humangenetik Universitätsklinikum Düsseldorf, Heinrich‐Heine‐Universität Düsseldorf Germany; 14 IUF‐Leibniz Research Institute for Environmental Medicine Düsseldorf Germany
  12. [12] 3 Institute of Structural Biology Helmholtz Zentrum München Neuherberg Germany; 4 Biomolecular NMR at Center for Integrated Protein Science Munich and Department Chemie Technische Universität München Garching Germany; 15 Department of Drug Technology and Pharmaceutical Biotechnology Faculty of Pharmacy Medical University of Warsaw Warsaw Poland

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 2, 2019, pág. 7
• Idioma: inglés
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• Resumen

  • Centrosome amplification is a hallmark of human cancers that can trigger cancer cell invasion. To survive, cancer cells cluster amplified extra centrosomes and achieve pseudobipolar division. Here, we set out to prevent clustering of extra centrosomes. Tubulin, by interacting with the centrosomal protein CPAP, negatively regulates CPAP‐dependent peri‐centriolar material recruitment, and concurrently microtubule nucleation. Screening for compounds that perturb CPAP–tubulin interaction led to the identification of CCB02, which selectively binds at the CPAP binding site of tubulin. Genetic and chemical perturbation of CPAP–tubulin interaction activates extra centrosomes to nucleate enhanced numbers of microtubules prior to mitosis. This causes cells to undergo centrosome de‐clustering, prolonged multipolar mitosis, and cell death. 3D‐organotypic invasion assays reveal that CCB02 has broad anti‐invasive activity in various cancer models, including tyrosine kinase inhibitor (TKI)‐resistant EGFR‐mutant non‐small‐cell lung cancers. Thus, we have identified a vulnerability of cancer cells to activation of extra centrosomes, which may serve as a global approach to target various tumors, including drug‐resistant cancers exhibiting high incidence of centrosome amplification.