Adapt or die: how eukaryotic cells respond to prolonged activation of the spindle assembly checkpoint.
Many cancer-treating compounds used in chemotherapies, the so-called antimitotics, target the mitotic spindle. Spindle defects in turn trigger activation of the SAC (spindle assembly checkpoint), a surveillance mechanism that transiently arrests cells in mitosis to provide the time for error correction. When the SAC is satisfied, it is silenced. However, after a variable amount of time, cells escape from the mitotic arrest, even if the SAC is not satisfied, through a process called adaptation or mitotic slippage. Adaptation weakens the killing properties of antimitotics, ultimately giving rise to resistant cancer cells. We summarize here the mechanisms underlying this process and propose a strategy to identify the factors involved using budding yeast as a model system. Inhibition of factors involved in SAC adaptation could have important therapeutic applications by potentiating the ability of antimitotics to cause cell death.
Brandeis University, 415 South Street, Waltham, MA 02454-9110, USA.
Valentina
V
Rossio
Elena
E
Galati
Simonetta
S
Piatti
D000222:Adaptation, Physiological; D000782:Aneuploidy; D050256:Antimitotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000378:metabolism; D005057:Eukaryotic Cells / Q000166:cytology / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D015739:Nocodazole / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects* / Q000378:metabolism*
D050256:Antimitotic Agents; D018797:Cell Cycle Proteins; D005656:Fungal Proteins; D015739:Nocodazole