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Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP

Oncogene volume 24, pages 6877–6889 (2005)Cite this article

Abstract

In TNF-related apoptosis-inducing ligand (TRAIL)-resistant glioma cells, co-treatment with nontoxic doses of sodium butyrate and TRAIL resulted in a marked increase of TRAIL-induced apoptosis. This combined treatment was also cytotoxic to glioma cells overexpressing Bcl-2 or Bcl-xL, but not to normal human astrocytes, thus offering an attractive strategy for safely treating resistant gliomas. Cotreatment with sodium butyrate facilitated completion of proteolytic processing of procaspase-3 that was partially blocked by treatment with TRAIL alone. We also found that treatment with sodium butyrate significantly decreased the protein levels of survivin and X-linked inhibitor of apoptosis protein (XIAP), two major caspase inhibitors. Overexpression of survivin and XIAP attenuated sodium butyrate-stimulated TRAIL-induced apoptosis, suggesting its involvement in conferring TRAIL resistance to glioma cells. Furthermore, the kinase activities of Cdc2 and Cdk2 were significantly decreased following sodium butyrate treatment, accompanying downregulation of cyclin A and cyclin B, as well as upregulation of p21. Forced expression of Cdc2 plus cyclin B, but not Cdk2 plus cyclin A, attenuated sodium butyrate/TRAIL-induced apoptosis, overriding sodium butyrate-mediated downregulation of survivin and XIAP. Therefore, Cdc2-mediated downregulation of survivin and XIAP by sodium butyrate may contribute to the recovery of TRAIL sensitivity in glioma cells.

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Acknowledgements

We 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 CrmA expression vector; and Professor T Tokuhisa (Chiba University) for a flag/survivin fusion protein expression vector; Professor Y Nomura (Oita Medical University) for XIAP expression vector; Dr S van den Heuvel (Massachusetts General Hospital) for plasmids expressing Cdc2 and Cdk2; Dr P Robbins (University of Pittsburgh) for plasmids expressing cyclin A and cyclin B; Dr DY Shin (Dankook University college of Medicine) for the reporter constructs containing the promoters of human cyclin A and cyclin B1; Dr B Vogelstein for human colon cancer cell lines, HCT116 wild-type cells and HCT116 p21−/− cells. This study was supported by grants from the National R & D Program for Cancer Control (2003), Ministry of Health & Welfare, Korea and the KOSEF/BDRC Ajou University (R11-1998-052-08009).

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Authors and Affiliations

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

    Eun Hee Kim, Hee Sue Kim & Kyeong Sook Choi

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

    Seung U Kim & Kyeong Sook Choi

  3. Division of Neurology, UBC Hospital, University of British Columbia, Vancouver, Canada

    Seung U Kim, Eun Joo Noh & Jong-Soo Lee

  4. Research Institute, National Cancer Center, South Korea

    Jong-Soo Lee

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Kim, E., Kim, H., Kim, S. et al. Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP. Oncogene 24, 6877–6889 (2005). https://doi.org/10.1038/sj.onc.1208851

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