Preferential killing of tetraploid tumor cells by targeting the mitotic kinesin Eg5.
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.
Rello-Varona
Santiago
S
INSERM U848, Institut Gustave Roussy, and Université de Paris 11, Villejuif, France.
Vitale
Ilio
I
Kepp
Oliver
O
Senovilla
Laura
L
Jemaá
Mohamed
M
Métivier
Didier
D
Castedo
Maria
M
Kroemer
Guido
G
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000235:genetics; D008938:Mitosis / Q000187:drug effects; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011123:Polyploidy; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D013871:Thiones / Q000494:pharmacology*
D000970:Antineoplastic Agents; C470243:KIF11 protein, human; D011799:Quinazolines; D034741:RNA, Small Interfering; D013871:Thiones; C518969:dimethylenastron; D016547:Kinesins