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AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol
Shubha Anand1, Sue Penrhyn-Lowe, Ashok R Venkitaraman
1CR UK Department of Oncology and The medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, United Kingdom.
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.
Insights
Elevated Aurora-A expression in epithelial cancers disrupts the mitotic spindle assembly checkpoint, leading to paclitaxel (Taxol) resistance. This promotes multinucleation and apoptosis resistance in cancer cells.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The serine-threonine kinase gene AURORA-A is frequently amplified in epithelial malignancies.
- Understanding the role of Aurora-A in cancer progression and treatment resistance is crucial.
Purpose of the Study:
- To investigate how elevated Aurora-A expression impacts mitotic spindle assembly and chemotherapy response.
- To elucidate the mechanism by which Aurora-A overexpression confers resistance to paclitaxel (Taxol).
Main Methods:
- Analysis of Aurora-A expression levels in epithelial malignancies.
- Cellular studies involving overexpression of Aurora-A.
- Investigation of mitotic spindle assembly, checkpoint activation (Mad2, BUB1), and cytokinesis.
- Assessment of paclitaxel (Taxol) sensitivity and apoptosis induction in cancer cell lines.
Main Results:
- Elevated Aurora-A overrides the spindle assembly checkpoint, allowing entry into anaphase despite defective spindle formation.
- Persistence of Mad2 at kinetochores indicates sustained checkpoint activation.
- Failure in cytokinesis leads to multinucleation, a phenotype reversed by BUB1 inhibition.
- Overexpression of Aurora-A induces resistance to paclitaxel (Taxol)-mediated apoptosis.
Conclusions:
- Aurora-A overexpression is a key driver of mitotic abnormalities and paclitaxel (Taxol) resistance in epithelial cancers.
- The findings link Aurora-A's oncogenic role to the disruption of spindle checkpoint control.
- Targeting Aurora-A may represent a therapeutic strategy to overcome chemotherapy resistance.