title: Peloruside A, a microtubule-stabilizing agent, induces aneuploidy in ovarian cancer cells.
abstract: To ensure proper chromosome segregation, mitosis is tightly regulated by the spindle assembly checkpoint (SAC). Low concentrations of microtubule-stabilizing agents can induce aneuploid populations of cells in the absence of G2/M block, suggesting pertubation of the spindle checkpoint. We investigated the effects of peloruside A, a microtubule-stabilizing agent, on expression levels of several key cell cycle proteins, MAD2, BUBR1, p55CDC and cyclin B1. Synchronized 1A9 ovarian carcinoma cells were allowed to progress through the cell cycle in the presence or absence of peloruside A. Co-immunoprecipitation and Western blotting were used to probe the cell cycle kinetics of MAD2 and BUBR1 dissociation from p55CDC. Using confocal microscopy, we investigated whether premature dissociation of MAD2 and BUBR1 at low (40 nM) but not high (100 nM) concentrations of peloruside A was caused by defects in the attachment of chromosomes to the mitotic spindle. An increased frequency of polar chromosomes was observed at low concentrations of peloruside A, suggesting that an increased frequency of pseudo-metaphase cells, which are not detected by the spindle assembly checkpoint, may be underlying the induction of aneuploidy.
authors.affiliation: School of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand.|Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand.|Volpara Solutions Limited, Level 12, 86 Victoria Street, Wellington, 6011, New Zealand.
authors.forename: Ariane
authors.initials: A
authors.lastname: Chan
authors.affiliation: Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand.|School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand.|Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute - Frederick, Frederick, MD, 21702, USA.
authors.forename: A Jonathan
authors.initials: AJ
authors.lastname: Singh
authors.affiliation: Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand.|School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Northcote
authors.affiliation: School of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand. john.h.miller@vuw.ac.nz.|Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand. john.h.miller@vuw.ac.nz.
authors.forename: John H
authors.initials: JH
authors.lastname: Miller
mesh_terms: D000782:Aneuploidy; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008870:Microtubules; D008938:Mitosis / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018797:Cell Cycle Proteins; D007783:Lactones; C414085:peloruside A
keywords: Aneuploidy; BUBR1; MAD2; Microtubule; Mitosis; Peloruside A; Spindle checkpoint; p55CDC