Universität zu Köln

Pannu, V., Rida, P. C. G., Celik, B., Turaga, R. C., Ogden, A., Cantuaria, G., Gopalakrishnan, J. and Aneja, R. (2014). Centrosome-declustering drugs mediate a two-pronged attack on interphase and mitosis in supercentrosomal cancer cells. Cell Death Dis., 5. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-4889

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Abstract

Classical anti-mitotic drugs have failed to translate their preclinical efficacy into clinical response in human trials. Their clinical failure has challenged the notion that tumor cells divide frequently at rates comparable to those of cancer cells in vitro and in xenograft models. Given the preponderance of interphase cells in clinical tumors, we asked whether targeting amplified centrosomes, which cancer cells carefully preserve in a tightly clustered conformation throughout interphase, presents a superior chemotherapeutic strategy that sabotages interphase-specific cellular activities, such as migration. Herein we have utilized supercentrosomal N1E-115 murine neuroblastoma cells as a test-bed to study interphase centrosome declustering induced by putative declustering agents, such as Reduced-9-bromonoscapine (RedBr-Nos), Griseofulvin and PJ-34. We found tight 'supercentrosomal' clusters in the interphase and mitosis of similar to 80% of patients' tumor cells with excess centrosomes. RedBr-Nos was the strongest declustering agent with a declustering index of 0.36 and completely dispersed interphase centrosome clusters in N1E-115 cells. Interphase centrosome declustering caused inhibition of neurite formation, impairment of cell polarization and Golgi organization, disrupted cellular protrusions and focal adhesion contacts-factors that are crucial prerequisites for directional migration. Thus our data illustrate an interphase-specific potential anti-migratory role of centrosome-declustering agents in addition to their previously acknowledged ability to induce spindle multipolarity and mitotic catastrophe. Centrosome-declustering agents counter centrosome clustering to inhibit directional cell migration in interphase cells and set up multipolar mitotic catastrophe, suggesting that disbanding the nuclear-centrosome-Golgi axis is a potential anti-metastasis strategy.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pannu, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rida, P. C. G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Celik, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Turaga, R. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ogden, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cantuaria, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gopalakrishnan, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Aneja, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-424004
DOI:	10.1038/cddis.2014.505
Journal or Publication Title:	Cell Death Dis.
Volume:	5
Date:	2014
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-4889
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHROMOSOME INSTABILITY; SPINDLE MULTIPOLARITY; AMPLIFICATION; INDUCTION; MIGRATION; VINCULIN; AGENTS; DERIVATIVES; INHIBITOR; INVASION Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42400