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Rottlerin sensitizes glioma cells to TRAIL-induced apoptosis by inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP

Oncogene volumeĀ 24,Ā pages 838ā€“849 (2005)Cite this article

Abstract

In the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant glioma cells, treatment with TRAIL in combination with subtoxic doses of rottlerin induced rapid apoptosis. While the proteolytic processing of procaspase-3 by TRAIL was partially blocked in these cells, treatment with rottlerin efficiently recovered TRAIL-induced activation of caspases. Treatment with rottlerin significantly decreased Cdc2 activity through the downregulation of cyclin A, cyclin B, and Cdc2 proteins, whereas the sensitizing effect of rottlerin on TRAIL-induced apoptosis was independent of PKCĪ“ activity. Furthermore, treatment with rottlerin downregulated the protein levels of survivin and X-chromosome-linked IAP (XIAP), two major caspase inhibitors. Forced expression of Cdc2 together with cyclin B attenuated rottlerin-potentiated TRAIL-induced apoptosis by over-riding the rottlerin-mediated downregulation of survivin and XIAP protein levels. Taken together, inhibition of Cdc2 activity and the subsequent downregulation of survivin and XIAP by subtoxic doses of rottlerin contribute to amplification of caspase cascades, thereby overcoming resistance of glioma cells to TRAIL-mediated apoptosis. Since rottlerin can sensitize Bcl-2- or Bcl-xL-overexpressing glioma cells but not human astrocytes to TRAIL-induced apoptosis, this combined treatment may offer an attractive strategy for safely treating resistant gliomas.

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Abbreviations

TRAIL:

TNF-related apoptosis-inducing ligand

PBS:

phosphate-buffered saline

PAGE:

polyacrylamide gel electrophoresis

SDSā€“PAGE:

sodium dodecyl sulfateā€“polyacrylamide gel electrophoresis

DN:

dominant negative

FLIP:

FLICE-inhibitory protein

IAP:

inhibitor of apoptosis

XIAP:

X-chromosome-linked IAP

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Acknowledgements

We thank Dr JF Mushinski for providing plasmids encoding WT PKCĪ“ and DN PKCĪ“ mutant (NIH). We also thank Professor A Strasser (The Walter and Eliza Hall Institute of Medical Research) for providing us with Bcl-2 and Bcl-xL expression vector; Professor VM Dixit (University of Michigan Medical School) for providing CrmA expression vector; Professor T Tokuhisa (Chiba University) for providing a flag/survivin fusion protein expression vector; Professor Y Nomura (Oita Medical University) for providing XIAP expression vector; Dr S van den Heuvel (Massachusetts General Hospital) for providing plasmids expressing Cdc2; and Dr P Robbins (University of Pittsburgh) for providing plasmids expressing cyclin A and cyclin B. This study was supported by a grant from the National R & D Program for Cancer Control (2003), Ministry of Health & Welfare, Republic of Korea and a grant from the KOSEF/BDRC Ajou University (R11-1998-052-08009).

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  1. Institute for Medical Sciences, Ajou University School of Medicine, Suwon, 442-749, South Korea

    Eun Hee KimĀ &Ā Kyeong Sook Choi

  2. Brain Disease Research Center, Ajou University School of Medicine, Suwon, 442-749, South Korea

    Seung U KimĀ &Ā Kyeong Sook Choi

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Kim, E., Kim, S. & Choi, K. Rottlerin sensitizes glioma cells to TRAIL-induced apoptosis by inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP. Oncogene 24, 838ā€“849 (2005). https://doi.org/10.1038/sj.onc.1208241

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