CDK1 inhibitors antagonize the immediate apoptosis triggered by spindle disruption but promote apoptosis following the subsequent rereplication and abnormal mitosis

Spindle-disrupting agents and CDK inhibitors are important cancer therapeutic agents. Spindle toxins activate the spindle-assembly checkpoint and lead to sustained activation of CDK1. Different published results indicate that CDK1 activity is either important or dispensable for the cytotoxicity asso...

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Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Tex.), 2008-05, Vol.7 (10), p.1449-1461
Main Authors: Chan, Ying Wai, Ma, Hoi Tang, Wong, Winnie, Ho, Chui Chui, On, Kin Fan, Poon, Randy Y.C.
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Apoptosis - physiology
Binding
Biology
Bioscience
Calcium
Cancer
CDC2 Protein Kinase - antagonists & inhibitors
Cell
Cycle
Enzyme Activation - physiology
Flow Cytometry
HeLa Cells
Humans
Immunoblotting
Landes
Mitosis - physiology
Mutagenesis, Site-Directed
Nocodazole - pharmacology
Oligonucleotides
Organogenesis
Proteins
Spindle Apparatus - drug effects
Tubulin Modulators - pharmacology
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Summary:Spindle-disrupting agents and CDK inhibitors are important cancer therapeutic agents. Spindle toxins activate the spindle-assembly checkpoint and lead to sustained activation of CDK1. Different published results indicate that CDK1 activity is either important or dispensable for the cytotoxicity associated with spindle disruption. Using live cell imaging and various approaches that uncoupled mitotic events, we show that apoptosis was induced by both prolonged nocodazole treatment as well as by inhibition of CDK1 activity after a transient nocodazole block. However, distinct mechanisms are involved in the two types of cell death. The massive apoptosis triggered by nocodazole treatment requires the continue activation of cyclin B1-CDK1 and is antagonized by premature mitotic slippage. By contrast, apoptosis induced by nocodazole followed by CDK inhibitors occurred after rereplication and multipolar mitosis of the subsequent cell cycle. The presence of dual mechanisms of cytotoxicity mediated by spindle disruption and CDK inhibition may reconcile the various apparent inconsistent published results. These data underscore the essential role of cyclin B1-CDK1 as the basis of apoptosis during mitotic arrest, and the role of mitotic slippage and abnormal mitosis for apoptosis at later stages.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.7.10.5880