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EMBO J. 2019 Jan 15;38(2). pii: e99876. doi: 10.15252/embj.201899876. Epub 2018 Dec 10.

Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells.

Author information

1
Institute für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, Düsseldorf, Germany.
2
Center for Molecular Medicine of the University of Cologne, Cologne, Germany.
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.
5
Assay Development and Screening Platform, Institute of molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
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.
9
Department of Chemistry, University of Cologne, Cologne, Germany.
10
Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
11
Bioanalytics, University Medical Center Goettingen, Goettingen, Germany.
12
Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Göttingen, Germany.
13
Institute of Pathology and Center for Molecular Medicine of the University of Cologne, Cologne, Germany.
14
IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
15
Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland.
16
Department of Biology, Georgia State University, Atlanta, GA, USA.
17
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
18
Institute für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, Düsseldorf, Germany jay.gopalakrishnan@hhu.de.

Abstract

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.

KEYWORDS:

CCB02; CPAP‐tubulin module; centrosome activation; centrosome clustering; centrosomes

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