Abstract
The cytotoxic effect of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is limited in many glioma cell lines. However, treatment with TRAIL in combination with subtoxic doses of roscovitine, a specific inhibitor of Cdc2 and Cdk2, induced rapid apoptosis in TRAIL-resistant glioma cells. Roscovitine could sensitize Bcl-2- or Bcl-xL-overexpressing glioma cells, but not human astrocytes, to TRAIL-induced apoptosis, offering an attractive strategy for safely treating resistant gliomas. Treatment with roscovitine significantly inhibited Cdc2 activity, and expression of a dominant-negative Cdc2 mutant sensitized glioma cells to TRAIL-induced apoptosis. While the proteolytic processing of procaspase-3 by TRAIL was partially blocked in U87MG and T98 glioma cells, treatment with roscovitine recovered TRAIL-induced activation of caspases very efficiently in these cells. We found that treatment with roscovitine or expression of a dominant-negative Cdc2 mutant downregulated the protein levels of survivin and XIAP, two major caspase inhibitors. Overexpression of survivin or XIAP attenuated the apoptosis induced by roscovitine and TRAIL. Taken together, these results suggest that downregulation of survivin and XIAP by subtoxic doses of roscovitine contributes to the amplification of caspase cascades, thereby overcoming glioma cell resistance to TRAIL-mediated apoptosis.
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Abbreviations
- TRAIL:
-
TNF-related apoptosis-inducing ligand
- GFAP:
-
glial fibrillary acidic protein
- PBS:
-
phosphate-buffered saline
- MTT:
-
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- PAGE:
-
polyacrylamide gel electrophoresis
- SDS–PAGE:
-
sodium dodecyl sulfate–polyacrylamide gel electrophoresis
- DN:
-
dominant negative
- FLIP:
-
FLICE-inhibitory protein
- IAP:
-
inhibitor of apoptosis
- XIAP:
-
X-chromosome-linked IAP
- FITC:
-
fluorescein isothiothyanate
- RT–PCR:
-
reverse transcriptase–polymerase chain reaction
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Acknowledgements
We thank Professor E Harlow (Massachusetts General Hospital Cancer Center) for generously providing the plasmids expressing HA-tagged dominant-negative Cdc2 and Cdk2 mutants. We also thank Professor A Strasser (The Walter and Eliza Hall Institute of medical Research) for providing us with the Bcl-2, Bcl-xL, and 19-kDa expression vector; and Professor VM Dixit (University of Michigan Medical School) for providing us with the CrmA expression vector. We thank Professor T Tokuhisa (Chiba University) for providing a flag/survivin fusion protein expression vector, and Professor Y Nomura (Oita Medical University) for providing the XIAP expression vector. This study was supported by a grant from the KOSEF/BDRC Ajou University (R11-1998-052-08005).
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Kim, E., Kim, S., Shin, D. et al. Roscovitine sensitizes glioma cells to TRAIL-mediated apoptosis by downregulation of survivin and XIAP. Oncogene 23, 446–456 (2004). https://doi.org/10.1038/sj.onc.1207025
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DOI: https://doi.org/10.1038/sj.onc.1207025
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