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Peloruside A, a microtubule-stabilizing agent, induces aneuploidy in ovarian cancer cells

Ariane Chan1,2,3, A Jonathan Singh2,4,5, Peter T Northcote2,4

  • 1School of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand.

Investigational New Drugs
|May 9, 2016
PubMed

Insights

Peloruside A, a microtubule stabilizer, can cause aneuploidy by disrupting the spindle assembly checkpoint (SAC). Low doses induce premature protein dissociation, leading to chromosome segregation errors and cell cycle defects.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Mitosis requires precise chromosome segregation, regulated by the spindle assembly checkpoint (SAC).
  • Microtubule-targeting agents can disrupt SAC function and lead to aneuploidy.
  • Peloruside A is a known microtubule-stabilizing agent.

Purpose of the Study:

  • To investigate the effects of peloruside A on key cell cycle proteins involved in SAC.
  • To determine if peloruside A perturbs chromosome attachment to the mitotic spindle.
  • To elucidate the mechanism by which peloruside A induces aneuploidy.

Main Methods:

  • Synchronization of 1A9 ovarian carcinoma cells.
  • Treatment with varying concentrations of peloruside A.
  • Co-immunoprecipitation and Western blotting to analyze protein interactions (MAD2, BUBR1, p55CDC).
  • Confocal microscopy to assess chromosome-spindle attachment.

Main Results:

  • Peloruside A affected expression levels of MAD2, BUBR1, p55CDC, and cyclin B1.
  • Low concentrations (40 nM) of peloruside A caused premature dissociation of MAD2 and BUBR1 from p55CDC.
  • Increased frequency of polar chromosomes and pseudo-metaphase cells observed at low peloruside A concentrations.
  • High concentrations (100 nM) did not induce these effects.

Conclusions:

  • Peloruside A, at low concentrations, disrupts SAC function by causing premature dissociation of checkpoint proteins.
  • This disruption leads to defects in chromosome attachment and segregation, resulting in aneuploidy.
  • The findings suggest a novel mechanism for peloruside A-induced aneuploidy via SAC evasion.
Keywords:
AneuploidyBUBR1MAD2MicrotubuleMitosisPeloruside ASpindle checkpointp55CDC

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