Cell death in leukemia: passenger protein regulation by topoisomerase inhibitors.
Etoposide is a potent inducer of mitotic catastrophe; a type of cell death resulting from aberrant mitosis. It is important in p53 negative cells where p53 dependent apoptosis and events at the G1 and G2 cell cycle checkpoints are compromised. Passenger proteins regulate many aspects of mitosis and siRNA interference or direct inhibition of Aurora B kinase results in mitotic catastrophe. However, there is little available data of clinical relevance in leukaemia models. Here, in p53 negative K562 myeloid leukemia cells, etoposide-induced mitotic catastrophe is shown to be time and/or concentration dependent. Survivin and Aurora remained bound to chromosomes. Survivin and Aurora were also associated with Cdk1 and were shown to form complexes, which in pull down experiments, included INCENP. There was no evidence of Aurora B kinase suppression. These data suggests etoposide will complement Aurora B kinase inhibitors currently in clinical trials for cancer.
Centre for Haematology, Institute of Cell and Molecular Sciences, Barts and The London School of Medicine and Dentistry, Queen Mary's, University of London, 4 Newark Street, London E1 2AT, UK.
Ulrike
U
Jahnke
Karen
K
Higginbottom
Adrian C
AC
Newland
Finbarr E
FE
Cotter
Paul D
PD
Allen
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D064107:Aurora Kinase B; D064127:Aurora Kinases; D016203:CDC2 Protein Kinase / Q000378:metabolism; D016923:Cell Death; D002877:Chromosomes, Human / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology*; D016195:G2 Phase; D006657:Histones / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D009363:Neoplasm Proteins / Q000032:analysis / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism; D000077022:Survivin; D059005:Topoisomerase II Inhibitors
D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D004791:Enzyme Inhibitors; D006657:Histones; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase