Defective G1-S cell cycle checkpoint function sensitizes cells to microtubule inhibitor-induced apoptosis.
Defective cell cycle checkpoint function has been linked to enhanced sensitivity of tumor cells to certain genotoxic agents. To determine whether loss of the G1-S checkpoint function would sensitize tumor cells to microtubule inhibitor (MTI)-induced apoptosis, we examined the effect of the MTIs, Taxol and vincristine, on the cell cycle kinetics and survival of two isogenic cell lines, HCT116 p21+/+ and HCT116 p21-/-, which differ only at the p21 locus. p21-deficient cells displayed a dose-dependent, enhanced chemosensitivity to MTIs in both monolayer and soft agar assays as well as in mice xenograft tumors. The increased sensitivity of the p21-deficient cells to MTIs correlated with prolonged cyclin B1/Cdc2 activity and the occurrence of endoreduplication. Furthermore, sensitivity of p53-deficient cells to MTI-induced apoptosis was significantly reduced by induction of ectopic p21 protein. The results suggest that the status of G1-S checkpoint function in tumor cells may be an important determinant in the efficacy of MTIs used clinically.
Stewart
Z A
ZA
Department of Biochemistry, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Mays
D
D
Pietenpol
J A
JA
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002277:Carcinoma / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004441:Ecdysterone / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D016193:G1 Phase / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D016196:S Phase / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology* / Q000627:therapeutic use
D000972:Antineoplastic Agents, Phytogenic; C534700:Ccnb1 protein, mouse; C493957:Cdkn1a protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D004441:Ecdysterone; D014750:Vincristine; C008999:ponasterone A; D016203:CDC2 Protein Kinase; D017239:Paclitaxel