English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT

Released

Journal Article

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

MPS-Authors
/persons/resource/persons131071

Mandad,  S.
Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society;

/persons/resource/persons15947

Urlaub,  H.
Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society;

External Resource
No external resources are shared
Fulltext (public)

3014423.pdf
(Publisher version), 13MB

Supplementary Material (public)
There is no public supplementary material available
Citation

Mariappan, A., Soni, K., Schorpp, K., Zhao, F., Minakar, A., Zheng, X., et al. (2018). Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells. The EMBO Journal, In press (e99876). doi:10.15252/embj.201899876.


Cite as: http://hdl.handle.net/21.11116/0000-0002-A918-5
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.