Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells.
The mitotic checkpoint has evolved to prevent chromosome mis-segregations by delaying mitosis when unattached chromosomes are present. Inducing severe chromosome segregation errors by ablating the mitotic checkpoint causes cell death. Here we have analyzed the consequences of gradual increases in chromosome segregation errors on the viability of tumor cells and normal human fibroblasts. Partial reduction of essential mitotic checkpoint components in four tumor cell lines caused mild chromosome mis-segregations, but no lethality. These cells were, however, remarkably more sensitive to low doses of taxol, which enhanced the amount and severity of chromosome segregation errors. Sensitization to taxol was achieved by reducing levels of Mps1 or BubR1, proteins having dual roles in checkpoint activation and chromosome alignment, but not by reducing Mad2, functioning solely in the mitotic checkpoint. Moreover, we find that untransformed human fibroblasts with reduced Mps1 levels could not be sensitized to sublethal doses of taxol. Thus, targeting the mitotic checkpoint and chromosome alignment simultaneously may selectively kill tumor cells by enhancing chromosome mis-segregations.
Department of Medical Oncology, Cancer Genomics Center, UMC Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
Aniek
A
Janssen
Geert J P L
GJ
Kops
René H
RH
Medema
D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D043171:Chromosomal Instability / Q000502:physiology*; D020090:Chromosome Segregation / Q000187:drug effects / Q000502:physiology*; D003114:Colony-Forming Units Assay; D004351:Drug Resistance / Q000235:genetics; D005347:Fibroblasts; D006801:Humans; D064246:Mad2 Proteins; D008856:Microscopy, Fluorescence; D017239:Paclitaxel / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism
D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D012097:Repressor Proteins; D011505:Protein-Tyrosine Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human; D017239:Paclitaxel