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

Authors
Kim, EH; Kim, SU; Choi, KS
Citation
Oncogene, 24(5):838-849, 2005
Journal Title
Oncogene
ISSN
0950-92321476-5594
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 PKCdelta 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.
MeSH terms
Acetophenones/pharmacology*Antigens, Neoplasm/geneticsApoptosis/drug effects*Apoptosis Regulatory ProteinsBenzopyrans/pharmacology*CDC2 Protein Kinase/antagonists & inhibitors*Caspases/antagonists & inhibitorsCell Line, TumorEnzyme Inhibitors/pharmacologyGlioma/pathology*HumansMembrane Glycoproteins/physiology*Microtubule-Associated Proteins/genetics*Neoplasm ProteinsProteins/genetics*TNF-Related Apoptosis-Inducing LigandTumor Necrosis Factor-alpha/physiology*X-Linked Inhibitor of Apoptosis Protein
DOI
10.1038/sj.onc.1208241
PMID
15531913
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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