A p34(cdc2) survival checkpoint in cancer

A checkpoint surveying the entry into mitosis responds to defects in spindle microtubule assembly/stability. This has been used to trigger apoptosis in cancer cells, but how the spindle checkpoint couples to the cell survival machinery has remained elusive. Here, we report that microtubule stabiliza...

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Bibliographic Details
Published in:Cancer cell 2002-07, Vol.2 (1), p.43
Main Authors: O'Connor, Daniel S, Wall, Nathan R, Porter, Andrew C G, Altieri, Dario C
Format: Article
Language:English
Subjects:
Adenine - analogs & derivatives
Adenine - therapeutic use
Animals
Antineoplastic Agents, Phytogenic - pharmacology
CDC2 Protein Kinase - metabolism
Cell Cycle - drug effects
Cell Survival - drug effects
Dose-Response Relationship, Drug
Enzyme Activation
Female
HeLa Cells
Humans
Inhibitor of Apoptosis Proteins
Mice
Mice, Knockout
Mice, SCID
Microtubule-Associated Proteins - genetics
Microtubule-Associated Proteins - metabolism
Neoplasm Proteins
Paclitaxel - pharmacology
Phosphorylation
Purines - pharmacology
Spindle Apparatus - physiology
Time Factors
Tumor Cells, Cultured
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Summary:A checkpoint surveying the entry into mitosis responds to defects in spindle microtubule assembly/stability. This has been used to trigger apoptosis in cancer cells, but how the spindle checkpoint couples to the cell survival machinery has remained elusive. Here, we report that microtubule stabilization engenders a survival pathway that depends on elevated activity of p34(cdc2) kinase and increased expression of the apoptosis inhibitor and mitotic regulator, survivin. Pharmacologic, genetic, or molecular ablation of p34(cdc2) kinase after microtubule stabilization resulted in massive apoptosis independent of p53, suppression of tumor growth, and indefinite survival without toxicity in mice. By ablating this survival checkpoint, inhibitors of p34(cdc2) kinase could safely improve the efficacy of microtubule-stabilizing agents used to treat common cancers.
ISSN:1535-6108
DOI:10.1016/S1535-6108(02)00084-3