Abstract
Small-molecule inhibitors of the Aurora A and B kinases interfere with mitotic centrosome function and disrupt the mitotic spindle assembly checkpoint resulting in polyploidization and apoptosis of proliferating cells. As such, several Aurora kinase inhibitors are at various stages of clinical development as anticancer agents. To identify candidate apoptosis-sensitizing genes that could be exploited in combination with Aurora kinase inhibitors in malignant glioma, we have carried out global gene expression analysis in a D54MG glioma cell derivative treated with three Aurora kinase inhibitors chosen for their distinctive selectivities: MLN8054 (Aurora A-selective), AZD1152 (Aurora B-selective), and VX-680 (Aurora A/B). The modulation of apoptotic gene expression by p53 under these conditions was ascertained, as p53 expression can be toggled on and off in this D54MG derivative by virtue of a stable, inducible, p53-targeting short hairpin RNA (D54MGshp53). This analysis identified the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor, TRAIL receptor 2 (TRAIL-R2), as an apoptosis-sensitizing gene induced selectively following inhibition of Aurora B. In glioma cell lines where TRAIL-R2 was induced following polyploidization, the sensitivity, kinetics, and magnitude of TRAIL-mediated apoptosis were enhanced. Our data shed light on the apoptotic program induced during polyploidization and suggest that TRAIL-R2 activation is a putative point of therapeutic intervention in combination with inhibitors of Aurora B.
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Abbreviations
- FACS:
-
fluorescence-activated cell sorting
- FADD:
-
Fas-associated death domain
- IPA:
-
Ingenuity Pathway Analysis
- PE:
-
phycoerythrin
- shRNA:
-
short hairpin RNA
- TRAIL:
-
tumor necrosis factor-related apoptosis-inducing ligand
- TRAIL-R1:
-
tumor necrosis factor-related apoptosis-inducing ligand receptor 1
- TRAIL-R2:
-
tumor necrosis factor-related apoptosis-inducing ligand receptor 2
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Acknowledgements
We thank Zhiqin Ji for synthesizing MLN8054 and AZD1152 and Douglas H Steinman for the synthesis of VX-680. We also thank Zehan Chen for technical assistance with the flow cytometric studies carried out here and Joel D Leverson, Chris Tse, and Steven K Davidsen for critical review of the manuscript.
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Li, J., Anderson, M., Tucker, L. et al. Inhibition of Aurora B kinase sensitizes a subset of human glioma cells to TRAIL concomitant with induction of TRAIL-R2. Cell Death Differ 16, 498–511 (2009). https://doi.org/10.1038/cdd.2008.174
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DOI: https://doi.org/10.1038/cdd.2008.174
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