Inactivation of the mitotic checkpoint as a determinant of the efficacy of microtubule-targeted drugs in killing human cancer cells.
Drugs that disrupt microtubule dynamics include some of the most important of cancer chemotherapies. While these drugs, which include paclitaxel (Taxol), are known to invoke the mitotic checkpoint, the factors that determine cancer cell killing remain incompletely characterized. Cells that are relatively resistant to killing by these drugs block robustly in mitosis, whereas cells sensitive to killing block only transiently in mitosis before undergoing nuclear fragmentation and death. Passage through mitosis was an absolute requirement of drug-induced death, because death was markedly reduced in cells blocked at both G(1)-S and G(2). Cell killing was at least in part linked to the absence or inactivation of BubR1, a kinetochore-associated phosphoprotein that mediates the mitotic checkpoint. Sensitivity to paclitaxel correlated with decreased BubR1 protein expression in human cancer cell lines, including those derived from breast and ovarian cancers. Silencing of BubR1 via RNA interference inactivated the mitotic checkpoint in drug-resistant cells, and reversed resistance to paclitaxel and nocodazole. Together, these results suggest that the mitotic checkpoint is an important determinant of the efficacy of microtubule-targeting drugs in killing cancer cells, potentially providing novel targets for increasing treatment efficacy.
Lee
Eric A
EA
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Keutmann
Michael K
MK
Dowling
Melissa L
ML
Harris
Eleanor
E
Chan
Gordon
G
Kao
Gary D
GD
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007399:Interphase / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology*; D015739:Nocodazole / Q000494:pharmacology; D009928:Organ Specificity; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D011494:Protein Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D017239:Paclitaxel; D015739:Nocodazole