The tubulin-depolymerising agent combretastatin-4 induces ectopic aster assembly and mitotic catastrophe in lung cancer cells H460

Chiara Cenciarelli, Caterina Tanzarella, Ilio Vitale, Claudio Pisano, Pasqualina Crateri, Stefania Meschini, Giuseppe Arancia, Antonio Antoccia

Research output: Contribution to journalArticle

Abstract

The relationship between microtubular dynamics, dismantling of pericentriolar components and induction of apoptosis was analysed after exposure of H460 non-small lung cancer cells to anti-mitotic drugs. The microtubule destabilising agent, combretastatin-A4 (CA-4) led to microtubular array disorganization, arrest in mitosis and abnormal metaphases, accompanied by the presence of numerous centrosome-independent "star-like" structures containing tubulin and aggregates of pericentrosomal matrix components like γ-tubulin, pericentrin and ninein, whereas the structural integrity of centrioles was not affected by treatment. On the contrary, in condition of prolonged exposure or high concentrations of CA-4 such aggregates never formed. Treatment with 7.5 nM CA-4, which produced a high frequency "star- like" aggregates, was accompanied by mitotic catastrophe commitment characterized by translocation of the proapoptotic Bim protein to mitochondria activation of caspases-3/9 and DNA fragmentation as a result of either prolonged metaphase arrest or attempt of cells to divide. Drug concentrations which fail to block cells at mitosis were also unable to activate apotosis. A detailed time-course analysis of cell cycle arrest and apoptosis indicated that after CA-4 washout the number of metaphases with "star-like" structures decreased as a function of time and arrested cells proceeded in anaphase. After 4 h, the multiple α- and γ-tubulin aggregates coalesced into two well-defined spindles in a bipolar mitotic spindle organization. Overall, our findings suggest that the maintenance of microtubular integrity plays a relevant role in stabilising the pericentriolar matrix, whose dismantling can be associated with apoptosis after exposure to microtubule depolymerising agents.

Original languageEnglish
Pages (from-to)659-669
Number of pages11
JournalApoptosis
Volume13
Issue number5
DOIs
Publication statusPublished - May 2008

Keywords

  • Bim
  • CA-4
  • Centrosome
  • Gamma-tubulin
  • Mitotic catastrophe
  • Ninein
  • Pericentrin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Cell Biology

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    Cenciarelli, C., Tanzarella, C., Vitale, I., Pisano, C., Crateri, P., Meschini, S., Arancia, G., & Antoccia, A. (2008). The tubulin-depolymerising agent combretastatin-4 induces ectopic aster assembly and mitotic catastrophe in lung cancer cells H460. Apoptosis, 13(5), 659-669. https://doi.org/10.1007/s10495-008-0200-2