Linked Life Data

11004677

Source:http://linkedlifedata.com/resource/pubmed/id/11004677

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2000-11-15
pubmed:abstractText
We investigated the cytotoxic responsiveness of 40 cell lines derived from representatives of the Ewing's sarcoma family of tumours (ESFT), i.e., Ewing's sarcoma (ES), peripheral primitive neuroectodermal tumour (pPNET) and Askin tumour (AT), to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Incubation with TRAIL at 100 ng/ml induced cell death at 24 hr in 19 of 26 ES, 11 of 12 pPNET and 2 of 2 AT cell lines. Half-maximal cell death concentrations (IC(50) values) varied from 0.1 to 20 ng/ml. TRAIL displayed potent cytotoxic activity against freshly derived ESFT cell isolates. Cytotoxicity was associated with phosphatidylserine expression and internucleosomal DNA fragmentation, features characteristic of apoptosis. The apoptotic programme in the sensitive ESFT VH-64 cell line revealed TRAIL-induced activation of FLICE/MACH1 (caspase-8) and CPP32/Yama/apopain (caspase-3) and processing of the prototype caspase substrate poly(ADP-ribose) polymerase. In addition, TRAIL provoked a collapse of the mitochondrial transmembrane potential (DeltaPsi(m)), parallelled by a reduction in ATP levels and release of cytochrome c from mitochondria into the cytosol. Inhibition of caspase-8 and caspase-3 by zIETDfmk and zDEVDfmk, respectively, substantially prevented TRAIL-induced apoptosis. However, zIETDfmk, but not zDEVDfmk, reduced TRAIL-mediated DeltaPsi(m) dissipation, indicating that TRAIL causes mitochondrial dysfunction through caspase-8 acting upstream of mitochondria. While macromolecule synthesis inhibitors (actinomycin D, cycloheximide) augmented susceptibility to TRAIL in TRAIL-responsive cell lines, these agents did not render TRAIL-resistant cell lines susceptible to TRAIL. However, the proteasome inhibitor MG132 sensitised to TRAIL in resistant cell lines. Collectively, these results show that TRAIL initiates effective death in the vast majority (80%) of cell lines derived from ESFT. Since TRAIL provoked cell death in ESFT ex vivo, this cytokine may be a promising drug for the treatment of ESFT in vivo.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0020-7136
pubmed:author
pubmed:copyrightInfo
Copyright 2000 Wiley-Liss, Inc.
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
88
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
252-9
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed-meshheading:11004677-Adenosine Triphosphate, pubmed-meshheading:11004677-Apoptosis, pubmed-meshheading:11004677-Apoptosis Regulatory Proteins, pubmed-meshheading:11004677-Bone Neoplasms, pubmed-meshheading:11004677-Cell Survival, pubmed-meshheading:11004677-Cytochrome c Group, pubmed-meshheading:11004677-Humans, pubmed-meshheading:11004677-Intracellular Membranes, pubmed-meshheading:11004677-Kinetics, pubmed-meshheading:11004677-Membrane Glycoproteins, pubmed-meshheading:11004677-Membrane Potentials, pubmed-meshheading:11004677-Mitochondria, pubmed-meshheading:11004677-Neuroectodermal Tumors, Primitive, pubmed-meshheading:11004677-Sarcoma, Ewing, pubmed-meshheading:11004677-TNF-Related Apoptosis-Inducing Ligand, pubmed-meshheading:11004677-Tumor Cells, Cultured, pubmed-meshheading:11004677-Tumor Necrosis Factor-alpha
pubmed:year
2000
pubmed:articleTitle
Apoptotic responsiveness of the Ewing's sarcoma family of tumours to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL).
pubmed:affiliation
Laboratory for Experimental Orthopaedic Research, Department of Orthopaedic Surgery, Westfälische-Wilhelms University, Münster, Germany. valen@uni-muenster.de
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't