title: Targeting the mitotic checkpoint to kill tumor cells.
abstract: One of the most common hallmarks of cancer cells is aneuploidy or an abnormal number of chromosomes. This abnormal chromosome content is a consequence of chromosome missegregation during mitosis, a defect that is seen more frequently in tumor cell divisions as in normal cell divisions. In fact, a large fraction of human tumors display a chromosome instable phenotype, meaning that they very frequently missegregate chromosomes. This can cause variegated aneuploidy within the tumor tissue. It has been argued that this hallmark of cancer could be exploited in anti-cancer therapies. Here we test this hypothesis by inactivation of the mitotic checkpoint through RNAi-mediated depletion of an essential checkpoint component, Mps1. The mitotic checkpoint delays segregation of chromosomes during mitosis until all chromosomes are properly attached to the mitotic spindle. Its inactivation will therefore lead to increased segregation errors. Indeed, we show that this can lead to increased cell death in tumor cells. We demonstrate that increased cell death is associated with a dramatic increase in segregation errors. This suggests that inhibition of the mitotic checkpoint might represent a useful anti-cancer strategy.
authors.affiliation: Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
authors.forename: Aniek
authors.initials: A
authors.lastname: Janssen
authors.forename: Geert J
authors.initials: GJ
authors.lastname: Kops
authors.forename: René H
authors.initials: RH
authors.lastname: Medema
mesh_terms: D000782:Aneuploidy; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002469:Cell Separation; D002470:Cell Survival; D005434:Flow Cytometry; D018816:Genes, cdc / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases; D034622:RNA Interference; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human