PMID- 11030149
OWN - NLM
STAT- MEDLINE
DCOM- 20001031
LR  - 20181130
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 19
IP  - 40
DP  - 2000 Sep 21
TI  - Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor 
      cells correlates with a loss of caspase-8 expression.
PG  - 4604-10
AB  - TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in 
      adult malignant glioma and various other human solid tumor models but not in 
      normal tissues. To characterize the TRAIL death pathway in childhood primitive 
      neuroectodermal brain tumor (PNET), 8 human PNET cell lines were tested for 
      TRAIL-induced apoptosis. TRAIL-sensitivity of the PNET cell lines was correlated 
      with mRNA expression levels of TRAIL, its agonistic (TRAIL-R1, TRAIL-R2) and 
      antagonistic (TRAIL-R3, TRAIL-R4) receptors, cellular FLICE-like inhibitory 
      protein (cFLIP), caspase-3 and caspase-8. Three of 8 PNET cell lines tested were 
      susceptible to TRAIL-induced apoptosis. Sensitivity to TRAIL-induced apoptosis 
      did not correlate with mRNA expression of TRAIL receptors or cFLIP. However, all 
      TRAIL-sensitive PNET cell lines expressed caspase-8 mRNA and protein, while none 
      of the five TRAIL-resistant PNET cell lines expressed caspase-8 protein. 
      Treatment with the methyltransferase inhibitor 5-aza-2'-deoxycytidine restored 
      mRNA expression of caspase-8 and TRAIL-sensitivity in formerly TRAIL-resistant 
      PNET cells, suggesting that gene methylation inhibits caspase-8 transcription in 
      these cells. We conclude, that loss of caspase-8 mRNA is an important mechanism 
      of TRAIL-resistance in PNET cells. Treatment with recombinant soluble TRAIL, 
      possibly in combination with methyltransferase inhibitors, represents a promising 
      therapeutic approach for PNET that deserves further investigation.
FAU - Grotzer, M A
AU  - Grotzer MA
AD  - Division of Oncology, The Children's Hospital of Philadelphia, Pennsylvania 
      19104, USA.
FAU - Eggert, A
AU  - Eggert A
FAU - Zuzak, T J
AU  - Zuzak TJ
FAU - Janss, A J
AU  - Janss AJ
FAU - Marwaha, S
AU  - Marwaha S
FAU - Wiewrodt, B R
AU  - Wiewrodt BR
FAU - Ikegaki, N
AU  - Ikegaki N
FAU - Brodeur, G M
AU  - Brodeur GM
FAU - Phillips, P C
AU  - Phillips PC
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (CASP8 and FADD-Like Apoptosis Regulating Protein)
RN  - 0 (CFLAR protein, human)
RN  - 0 (Carrier Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Protein Synthesis Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Neoplasm)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Recombinant Proteins)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNFSF10 protein, human)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 776B62CQ27 (Decitabine)
RN  - 98600C0908 (Cycloheximide)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases)
RN  - EC 3.4.22.- (CASP8 protein, human)
RN  - EC 3.4.22.- (CASP9 protein, human)
RN  - EC 3.4.22.- (Caspase 8)
RN  - EC 3.4.22.- (Caspase 9)
RN  - EC 3.4.22.- (Caspases)
RN  - M801H13NRU (Azacitidine)
SB  - IM
MH  - Adult
MH  - Antimetabolites, Antineoplastic/pharmacology
MH  - Apoptosis/*drug effects
MH  - Apoptosis Regulatory Proteins
MH  - Azacitidine/analogs & derivatives/pharmacology
MH  - CASP8 and FADD-Like Apoptosis Regulating Protein
MH  - Carrier Proteins/physiology
MH  - Caspase 8
MH  - Caspase 9
MH  - Caspases/biosynthesis/deficiency/genetics/*physiology
MH  - Child
MH  - Cycloheximide/pharmacology
MH  - DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors
MH  - DNA Methylation/drug effects
MH  - Decitabine
MH  - Drug Resistance
MH  - Enzyme Induction
MH  - Enzyme Inhibitors/pharmacology
MH  - *Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - *Intracellular Signaling Peptides and Proteins
MH  - Jurkat Cells/drug effects/metabolism
MH  - Membrane Glycoproteins/*pharmacology
MH  - Neoplasm Proteins/biosynthesis/deficiency/genetics/*physiology
MH  - Neuroectodermal Tumors, Primitive/enzymology/*pathology
MH  - Protein Synthesis Inhibitors/pharmacology
MH  - RNA, Messenger/biosynthesis
MH  - RNA, Neoplasm/biosynthesis
MH  - Receptors, Tumor Necrosis Factor/drug effects
MH  - Recombinant Proteins/pharmacology
MH  - TNF-Related Apoptosis-Inducing Ligand
MH  - Transcription, Genetic
MH  - Tumor Cells, Cultured/drug effects/enzymology
MH  - Tumor Necrosis Factor-alpha/*pharmacology
EDAT- 2000/10/13 11:00
MHDA- 2001/02/28 10:01
CRDT- 2000/10/13 11:00
PHST- 2000/10/13 11:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2000/10/13 11:00 [entrez]
AID - 10.1038/sj.onc.1203816 [doi]
PST - ppublish
SO  - Oncogene. 2000 Sep 21;19(40):4604-10. doi: 10.1038/sj.onc.1203816.