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.