A novel microtubule-modulating noscapinoid triggers apoptosis by inducing spindle multipolarity via centrosome amplification and declustering

P. Karna, P. C G Rida, V. Pannu, K. K. Gupta, William Dalton, H. Joshi, V. W. Yang, J. Zhou, R. Aneja

Research output: Contribution to journalArticle

Abstract

We have previously shown that a non-toxic noscapinoid, EM011 binds tubulin without altering its monomer/polymer ratio. EM011 is more active than the parent molecule, noscapine, in inducing G2/M arrest, inhibiting cellular proliferation and tumor growth in various human xenograft models. However, the mechanisms of mitotic-block and subsequent cell death have remained elusive. Here, we show that EM011-induced attenuation of microtubule dynamics was associated with impaired association of microtubule plus-end tracking proteins, such as EB1 and CLIP-170. EM011 treatment then led to the formation of multipolar spindles containing 'real' centrioles indicating drug-induced centrosome amplification and persistent centrosome declustering. Centrosome amplification was accompanied by an upregulation of Aurora A and Plk4 protein levels, as well as a surge in the kinase activity of Aurora A, suggesting a deregulation of the centrosome duplication cycle. Cell-cycle phase-specific experiments showed that the 'cytotoxicity-window' of the drug encompasses the late S-G2 period. Drug-treatment, excluding S-phase, not only resulted in lower sub-G1 population but also attenuated centrosome amplification and spindle multipolarity, suggesting that drug-induced centrosome amplification is essential for maximal cell death. Subsequent to a robust mitotic arrest, EM011-treated cells displayed diverse cellular fates suggesting a high degree of intraline variation. Some 'apoptosis-evasive' cells underwent aberrant cytokinesis to generate rampant aneuploidy that perhaps contributed to drug-induced cell death. These data indicate that spindle multipolarity induction by means of centrosome amplification has an exciting chemotherapeutic potential that merits further investigation.

Original languageEnglish (US)
Pages (from-to)632-644
Number of pages13
JournalCell Death and Differentiation
Volume18
Issue number4
DOIs
StatePublished - Apr 1 2011
Externally publishedYes

Fingerprint

Centrosome
Microtubules
Apoptosis
Cell Death
Pharmaceutical Preparations
S Phase
Noscapine
Aurora Kinase A
Centrioles
Cytokinesis
Aneuploidy
Tubulin
Heterografts
Cell Cycle
Polymers
Proteins
Up-Regulation
Cell Proliferation
Growth
Population

Keywords

  • aneuploidy
  • apoptosis
  • centrosome amplification
  • centrosome declustering
  • microtubule dynamics
  • tubulin-binding agent

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

A novel microtubule-modulating noscapinoid triggers apoptosis by inducing spindle multipolarity via centrosome amplification and declustering. / Karna, P.; Rida, P. C G; Pannu, V.; Gupta, K. K.; Dalton, William; Joshi, H.; Yang, V. W.; Zhou, J.; Aneja, R.

In: Cell Death and Differentiation, Vol. 18, No. 4, 01.04.2011, p. 632-644.

Research output: Contribution to journalArticle

Karna, P. ; Rida, P. C G ; Pannu, V. ; Gupta, K. K. ; Dalton, William ; Joshi, H. ; Yang, V. W. ; Zhou, J. ; Aneja, R. / A novel microtubule-modulating noscapinoid triggers apoptosis by inducing spindle multipolarity via centrosome amplification and declustering. In: Cell Death and Differentiation. 2011 ; Vol. 18, No. 4. pp. 632-644.
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AU - Gupta, K. K.

AU - Dalton, William

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AU - Yang, V. W.

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