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Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents

Masayuki Nitta1, Osamu Kobayashi, Shinobu Honda

  • 1Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, University of Kumamoto, 1-1-1 Honjo, Kumamoto 860-8556, Japan.

Oncogene
|June 29, 2004
PubMed

Insights

DNA-damaging agents cause mitotic catastrophe in cancer cells. In p53-deficient cells, spindle checkpoint activation prevents cell death, leading to therapeutic resistance.

Area of Science:

  • Cell biology
  • Cancer research
  • Molecular oncology

Background:

  • Mitotic catastrophe is a key cell death pathway induced by DNA-damaging antineoplastic agents.
  • Defects in cell cycle checkpoints (G1, G2) in cancer cells allow entry into mitosis with DNA damage.

Purpose of the Study:

  • To characterize the dynamics of mitotic catastrophe in p53-deficient cancer cells treated with DNA-damaging agents.
  • To investigate the role of the spindle checkpoint in this process.

Main Methods:

  • Utilized p53-deficient cancer cells.
  • Administered DNA-damaging agents.
  • Observed cell cycle progression and cell death.
  • Performed RNA interference for BubR1 and Mad2 to suppress spindle checkpoint function.

Main Results:

  • p53-deficient cells with DNA damage arrested transiently at metaphase for over 10 hours without chromosome segregation.
  • The spindle checkpoint, indicated by BubR1 kinetochore localization, appeared activated.
  • Suppression of the spindle checkpoint led to escape from mitotic catastrophe and abnormal mitosis.

Conclusions:

  • Spindle checkpoint activation is a critical event in metaphase arrest during DNA-induced mitotic catastrophe in p53-deficient cells.
  • Dysfunction of the spindle checkpoint contributes to resistance against DNA-damaging therapeutic agents in these cancer cells.

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