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Mariappan, A.* ; Soni, K. ; Schorpp, K.K. ; Zhao, F.* ; Minakar, A.* ; Zheng, X.* ; Mandad, S.* ; Macheleidt, I.* ; Ramani, A.* ; Kubelka, T.* ; Dawidowski, M. ; Golfmann, K.* ; Wason, A.* ; Yang, C.* ; Simons, J.* ; Schmalz, H.G.* ; Hyman, A.A.* ; Aneja, R.* ; Ullrich, R.* ; Urlaub, H.* ; Odenthal, M.* ; Büttner, R.* ; Li, H.* ; Sattler, M. ; Hadian, K. ; Gopalakrishnan, J.*

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

EMBO J. 37:e99876 (2019)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Ccb02 ; Centrosome Activation ; Centrosome Clustering ; Centrosomes ; Cpap-tubulin Module; Microtubule Nucleation; Functional-characterization; Lung-cancer; Cycle; Identification; Protein; Kinase; Phosphorylation; Amplification; Resistance
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Zeitschrift EMBO Journal, The
Quellenangaben Band: 37, Heft: 23, Seiten: , Artikelnummer: e99876 Supplement: ,
Verlag Wiley
Verlagsort Heidelberg, Germany
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
Institute of Molecular Toxicology and Pharmacology (TOXI)