Document Detail

Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apotosis in human malignant glioma cells.
MedLine Citation:
PMID:  11221847     Owner:  NLM     Status:  MEDLINE    
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially triggers apoptosis in tumor cells versus normal cells, thus providing a therapeutic potential. In this study, we examined a large panel of human malignant glioma cell lines and primary cultures of normal human astrocytes for their sensitivity to TRAIL. Of 13 glioma cell lines, 3 were sensitive (80-100% death), 4 were partially resistant (30-79% death), and 6 were resistant (< 30% death). Normal astrocytes were also resistant. TRAIL-induced cell death was characterized by activation of caspase-8 and -3, poly(ADP-ribose) polymerase cleavage, and DNA fragmentation. Decoy receptor (DcR1 and DcR2) expression was limited in the glioma cell lines and did not correlate with TRAIL sensitivity. Both sensitive and resistant cell lines expressed TRAIL death receptor (DR5), adapter protein Fas-associated death domain (FADD), and caspase-8; but resistant cell lines expressed 2-fold higher levels of the apoptosis inhibitor phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes-15 kDa (PED/PEA-15). In contrast, cellular FADD-like IL-1beta-converting enzyme-like inhibitory protein (cFLIP) expression was similar in sensitive and resistant cells. Transfection of sense PED/PEA-15 cDNA in sensitive cells resulted in cell resistance, whereas transfection of antisense in resistant cells rendered them sensitive. Inhibition of protein kinase C (PKC) activity restored TRAIL sensitivity in resistant cells, suggesting that PED/ PEA-15 function might be dependent on PKC-mediated phosphorylation. In summary, TRAIL induces apoptosis in > 50% of glioma cell lines, and this killing occurs through activation of the DR pathway. This caspase-8-induced apoptotic cascade is regulated by intracellular PED/PEA-15, but not by cFLIP or decoy receptors. This pathway may be exploitable for glioma and possibly for other cancer therapies.
C Hao; F Beguinot; G Condorelli; A Trencia; E G Van Meir; V W Yong; I F Parney; W H Roa; K C Petruk
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  61     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2001 Feb 
Date Detail:
Created Date:  2001-02-26     Completed Date:  2001-03-15     Revised Date:  2012-02-22    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1162-70     Citation Subset:  IM    
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.
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MeSH Terms
Apoptosis / drug effects*,  physiology
Apoptosis Regulatory Proteins
Astrocytes / cytology,  drug effects
CASP8 and FADD-Like Apoptosis Regulating Protein
Carrier Proteins / biosynthesis
Caspase 8
Caspase 9
Caspases / metabolism,  physiology
Cells, Cultured
Enzyme Activation
GPI-Linked Proteins
Glioma / genetics,  metabolism,  pathology*
Intracellular Signaling Peptides and Proteins*
Membrane Glycoproteins / pharmacology*,  physiology
Oligodeoxyribonucleotides, Antisense / genetics,  pharmacology
Phosphoproteins / genetics
Protein Synthesis Inhibitors / pharmacology
Receptors, Tumor Necrosis Factor / biosynthesis
Recombinant Proteins / pharmacology
TNF-Related Apoptosis-Inducing Ligand
Tumor Cells, Cultured
Tumor Necrosis Factor Decoy Receptors
Tumor Necrosis Factor-alpha / pharmacology*,  physiology
Grant Support
1R01CA/HL86335-01/CA/NCI NIH HHS; 1R21NS/HD41403-01/NS/NINDS NIH HHS; E.0896//Telethon
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/CASP8 and FADD-Like Apoptosis Regulating Protein; 0/CFLAR protein, human; 0/Carrier Proteins; 0/GPI-Linked Proteins; 0/Intracellular Signaling Peptides and Proteins; 0/Membrane Glycoproteins; 0/Oligodeoxyribonucleotides, Antisense; 0/PEA15 protein, human; 0/Phosphoproteins; 0/Protein Synthesis Inhibitors; 0/Receptors, Tumor Necrosis Factor; 0/Recombinant Proteins; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFRSF10C protein, human; 0/TNFSF10 protein, human; 0/Tumor Necrosis Factor Decoy Receptors; 0/Tumor Necrosis Factor-alpha; EC 3.4.22.-/CASP8 protein, human; EC 3.4.22.-/CASP9 protein, human; EC 3.4.22.-/Caspase 8; EC 3.4.22.-/Caspase 9; EC 3.4.22.-/Caspases

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