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 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.
O'Connor
Daniel S
DS
Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, Connecticut 06536, USA.
Wall
Nathan R
NR
Porter
Andrew C G
AC
Altieri
Dario C
DC
D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D011687:Purines / Q000494:pharmacology; D008941:Spindle Apparatus / Q000502:physiology*; D000077022:Survivin; D013997:Time Factors; D014407:Tumor Cells, Cultured
C471843:6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine; D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011687:Purines; D000077022:Survivin; D016203:CDC2 Protein Kinase; D000225:Adenine; D017239:Paclitaxel