AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol

Cancer Cell. 2003 Jan;3(1):51-62. doi: 10.1016/s1535-6108(02)00235-0.

Abstract

The serine-threonine kinase gene AURORA-A is commonly amplified in epithelial malignancies. Here we show that elevated Aurora-A expression at levels that reflect cancer-associated gene amplification overrides the checkpoint mechanism that monitors mitotic spindle assembly, inducing resistance to the chemotherapeutic agent paclitaxel (Taxol). Cells overexpressing Aurora-A inappropriately enter anaphase despite defective spindle formation, and the persistence of Mad2 at the kinetochores, marking continued activation of the spindle assembly checkpoint. Mitosis is subsequently arrested by failure to complete cytokinesis, resulting in multinucleation. This abnormality is relieved by an inhibitory mutant of BUB1, linking the mitotic abnormalities provoked by Aurora-A overexpression to spindle checkpoint activity. Consistent with this conclusion, elevated Aurora-A expression causes resistance to apoptosis induced by Taxol in a human cancer cell line.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Apoptosis / drug effects
  • Aurora Kinase A
  • Aurora Kinases
  • Blotting, Western
  • Cells, Cultured
  • Drug Resistance, Neoplasm / genetics*
  • Embryo, Mammalian
  • Fibroblasts
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Amplification*
  • Genes, cdc*
  • HeLa Cells
  • Humans
  • Mice
  • Mitosis / physiology*
  • Mutation
  • Paclitaxel / pharmacology
  • Protein Kinases / genetics
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / genetics*
  • Spindle Apparatus / physiology
  • Transfection

Substances

  • Antineoplastic Agents, Phytogenic
  • Protein Kinases
  • Aurka protein, mouse
  • Aurora Kinase A
  • Aurora Kinases
  • BUB1 protein, human
  • Bub1 protein, mouse
  • Bub1 spindle checkpoint protein
  • Protein-Serine-Threonine Kinases
  • Paclitaxel