Mariappan, Aruljothi, Soni, Komal, Schorpp, Kenji, Zhao, Fan, Minakar, Amin, Zheng, Xiangdong, Mandad, Sunit, Macheleidt, Iris, Ramani, Anand, Kubelka, Tomas ORCID: 0000-0003-1881-5171, Dawidowski, Maciej ORCID: 0000-0002-7262-5718, Golfmann, Kristina, Wason, Arpit, Yang, Chunhua, Simons, Judith, Schmalz, Hans-Guenther ORCID: 0000-0003-0489-1827, Hyman, Anthony A., Aneja, Ritu, Ullrich, Roland, Urlaub, Henning, Odenthal, Margarete, Buettner, Reinhardt, Li, Haitao ORCID: 0000-0001-6741-293X, Sattler, Michael ORCID: 0000-0002-1594-0527, Hadian, Kamyar and Gopalakrishnan, Jay (2019). Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells. Embo J., 38 (2). HOBOKEN: WILEY. ISSN 1460-2075

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mariappan, AruljothiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soni, KomalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schorpp, KenjiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhao, FanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Minakar, AminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zheng, XiangdongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mandad, SunitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Macheleidt, IrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramani, AnandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubelka, TomasUNSPECIFIEDorcid.org/0000-0003-1881-5171UNSPECIFIED
Dawidowski, MaciejUNSPECIFIEDorcid.org/0000-0002-7262-5718UNSPECIFIED
Golfmann, KristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wason, ArpitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, ChunhuaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simons, JudithUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmalz, Hans-GuentherUNSPECIFIEDorcid.org/0000-0003-0489-1827UNSPECIFIED
Hyman, Anthony A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aneja, RituUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullrich, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Urlaub, HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odenthal, MargareteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, HaitaoUNSPECIFIEDorcid.org/0000-0001-6741-293XUNSPECIFIED
Sattler, MichaelUNSPECIFIEDorcid.org/0000-0002-1594-0527UNSPECIFIED
Hadian, KamyarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gopalakrishnan, JayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-159188
DOI: 10.15252/embj.201899876
Journal or Publication Title: Embo J.
Volume: 38
Number: 2
Date: 2019
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1460-2075
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Organic Chemistry
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MICROTUBULE NUCLEATION; FUNCTIONAL-CHARACTERIZATION; LUNG-CANCER; CYCLE; IDENTIFICATION; PROTEIN; KINASE; PHOSPHORYLATION; AMPLIFICATION; RESISTANCEMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15918

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