Preferential killing of tetraploid tumor cells by targeting the mitotic kinesin Eg5

Santiago Rello-Varona, Ilio Vitale, Oliver Kepp, Laura Senovilla, Mohamed Jemaá, Didier Métivier, Maria Castedo, Guido Kroemer

Research output: Contribution to journalArticlepeer-review

Abstract

Tetraploid cells may constitute a metastable intermediate between normal euploidy and cancer-associated aneuploidy. Tetraploid cells are relatively more resistant against DNA damaging agents and are genetically unstable, due to their tendency towards multipolar, asymmetric division. Therefore, it is important to develop strategies for the selective removal of tetraploid cells. Here, we show that targeting the mitotic kinesin Eg5 (also known as kinesin spindle protein, KSP) by a small interfering RNA (siRNA) or by the pharmacological inhibitor dimethylenastron (DIMEN) kills tetraploid tumor cells more efficiently than their diploid precursors. Cell death occurs after an attempt of monoastral mitosis that, in diploid cells, is followed by a prolonged mitotic arrest and morphological reversion to the interphase, with a 4n DNA content. In contrast, DIMEN-treated tetraploid cells exhibit a shorter mitotic arrest, bipolar or multipolar karyokinesis, followed by apoptosis of the daughter cells, as assessed by fluorescence videomicroscopy of cells that express a histone 2B-GFP fusion construct to monitor their chromosomes. Cell death occurred with hallmarks of apoptosis, namely loss of the mitochondrial transmembrane potential and terminal chromatin compaction. In conclusion, tetraploid cells are particular vulnerable to undergo mitotic catastrophe after genetic or pharmacological inhibition of Eg5.

Original languageEnglish
Pages (from-to)1030-1035
Number of pages6
JournalCell Cycle
Volume8
Issue number7
Publication statusPublished - Apr 1 2009

Keywords

  • Apoptosis
  • Dimethylenastron
  • Kinesin spindle protein
  • Mitotic catastrophe
  • Monoastral mitosis

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

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