Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells.
Animals
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Centrosome
/ drug effects
Drug Screening Assays, Antitumor
Female
HeLa Cells
Humans
Mice
Microtubule-Associated Proteins
/ metabolism
Neoplasms
/ drug therapy
Protein Binding
/ drug effects
Small Molecule Libraries
/ administration & dosage
Tubulin
/ metabolism
Xenograft Model Antitumor Assays
CCB02
CPAP‐tubulin module
centrosome activation
centrosome clustering
centrosomes
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
15 01 2019
15 01 2019
Historique:
received:
22
05
2018
revised:
11
10
2018
accepted:
18
10
2018
pubmed:
12
12
2018
medline:
27
12
2019
entrez:
12
12
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30530478
pii: embj.201899876
doi: 10.15252/embj.201899876
pmc: PMC6331730
pii:
doi:
Substances chimiques
CENPJ protein, human
0
Microtubule-Associated Proteins
0
Small Molecule Libraries
0
Tubulin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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