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Caffeine promotes apoptosis in mitotic spindle checkpoint-arrested cells
Brian Gabrielli1, Yu Qian Chau, Nichole Giles
1Cancer Biology Program, Centre for Immunology and Cancer Research, University of Queensland, Brisbane, Queensland 4102, Australia. bgabrielli@cicr.uq.edu.au
The Journal of Biological Chemistry
|December 22, 2006
Summary
Caffeine induces apoptosis in cells arrested by the spindle assembly checkpoint by inhibiting PAK1, a key anti-apoptotic protein. This reveals the spindle checkpoint
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- The spindle assembly checkpoint (SAC) prevents chromosome missegregation during mitosis.
- SAC-arrested cells normally delay mitotic exit or undergo apoptosis.
- Mechanisms linking SAC arrest to apoptosis are not fully understood.
Purpose of the Study:
- To identify molecular components mediating apoptosis in SAC-arrested cells.
- To investigate caffeine's role in triggering apoptosis in these cells.
- To elucidate the function of PAK1 in SAC-induced apoptosis.
Main Methods:
- Caffeine treatment of SAC-arrested cells.
- Analysis of apoptosis, cyclin B1 degradation, CDK1 activity, and MPM-2 staining.
- Assessment of MAD2 kinetochore localization.
- Proteasome activity inhibition.
- PAK1 knockdown experiments.
Main Results:
- Caffeine induced >40% apoptosis in SAC-arrested cells within 5 hours.
- Caffeine triggered cyclin B1 degradation and reduced CDK1 activity.
- Continued SAC function was essential for caffeine-induced apoptosis.
- PAK1 was identified as a caffeine target with an anti-apoptotic role.
Conclusions:
- The spindle checkpoint regulates both mitotic exit and apoptosis.
- PAK1 acts as an anti-apoptotic factor in SAC-arrested cells.
- Caffeine promotes apoptosis by inhibiting PAK1 during SAC arrest.
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