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Inhibition of CPAP –tubulin interaction prevents proliferation of centrosome‐amplified cancer cells
Author(s) -
Mariappan Aruljothi,
Soni Komal,
Schorpp Kenji,
Zhao Fan,
Minakar Amin,
Zheng Xiangdong,
Mandad Sunit,
Macheleidt Iris,
Ramani Anand,
Kubelka Tomáš,
Dawidowski Maciej,
Golfmann Kristina,
Wason Arpit,
Yang Chunhua,
Simons Judith,
Schmalz HansGünther,
Hyman Anthony A,
Aneja Ritu,
Ullrich Roland,
Urlaub Henning,
Odenthal Margarete,
Büttner Reinhardt,
Li Haitao,
Sattler Michael,
Hadian Kamyar,
Gopalakrishnan Jay
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201899876
Subject(s) - beijing , chinese academy of sciences , china , library science , biological sciences , biology , political science , computational biology , computer science , law
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 CCB 02, 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 CCB 02 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.