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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.

Authors
Kim, EH; Kim, HS; Kim, SU; Noh, EJ; Lee, JS; Choi, K
Citation
Oncogene, 24(46):6877-6889, 2005
Journal Title
Oncogene
ISSN
0950-92321476-5594
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.
MeSH terms
Apoptosis/physiology*Apoptosis Regulatory Proteins/physiology*Astrocytes/cytologyBase SequenceButyric Acid/pharmacology*CDC2 Protein Kinase/antagonists & inhibitors*Cell Line, TumorCyclin-Dependent Kinase 2/antagonists & inhibitorsDNA PrimersDown-Regulation/physiology*Enzyme Inhibitors/pharmacologyGlioma/metabolismGlioma/pathology*Histone Deacetylase InhibitorsHumansMembrane Glycoproteins/physiology*Microtubule-Associated Proteins/physiology*Neoplasm Proteins/physiology*Reverse Transcriptase Polymerase Chain ReactionTNF-Related Apoptosis-Inducing LigandTumor Necrosis Factor-alpha/physiology*X-Linked Inhibitor of Apoptosis Protein/physiology*
DOI
10.1038/sj.onc.1208851
PMID
16007142
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Neurology
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
김, 승업최, 경숙
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