Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2000-2-28
pubmed:abstractText
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to exert potent cytotoxic activity against many tumor cell lines but not against normal cells. It has been hypothesized that this difference in TRAIL sensitivity between normal and transformed cells might be due to the expression of the non-death-inducing TRAIL receptors (TRAIL-R) TRAIL-R3 and TRAIL-R4, presumably by competition for limited amounts of TRAIL. To assess the regulation of resistance versus sensitivity to TRAIL in primary as well as transformed keratinocytes, we examined TRAIL sensitivity, TRAIL receptor expression, and intracellular signaling events induced by TRAIL. Although TRAIL induced apoptosis in primary as well as transformed keratinocytes, a marked difference in sensitivity could be observed with primary keratinocytes (PK) being 5-fold less sensitive to TRAIL than transformed keratinocytes (TK). Yet both cell types exhibited similar TRAIL receptor surface expression, suggesting that expression of TRAIL-R3 and TRAIL-R4 may not be the main regulator of sensitivity to TRAIL. Biochemical analysis of the signaling events induced by TRAIL revealed that PK could be sensitized for TRAIL and, similarly, for TRAIL-R1- and TRAIL-R2-specific apoptosis by pretreatment of the cells with cycloheximide (CHX). This sensitization concomitantly resulted in processing of caspase-8, which did not occur in TRAIL-resistant PK. These data indicate that an early block of TRAIL-induced apoptosis was present in PK compared with TK or PK treated with CHX. Interestingly, cellular FLICE inhibitory protein (cFLIP) levels, high in PK and low in TK and several other squamous cell carcinoma cell lines, decreased rapidly after treatment of PK with CHX, correlating with the increase in TRAIL sensitivity and caspase-8 processing. Furthermore, ectopic expression of cFLIP long (cFLIP(L)) in TK by transfection with a cFLIP(L) expression vector resulted in resistance to TRAIL-mediated apoptosis of these cells. Thus, our results demonstrate that TRAIL sensitivity in PK is primarily regulated at the intracellular level rather than at the receptor level.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Apoptosis Regulatory Proteins, http://linkedlifedata.com/resource/pubmed/chemical/CASP8 and FADD-Like Apoptosis..., http://linkedlifedata.com/resource/pubmed/chemical/CASP8 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/CASP9 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/CFLAR protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Caspase 8, http://linkedlifedata.com/resource/pubmed/chemical/Caspase 9, http://linkedlifedata.com/resource/pubmed/chemical/Caspases, http://linkedlifedata.com/resource/pubmed/chemical/Cycloheximide, http://linkedlifedata.com/resource/pubmed/chemical/GPI-Linked Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides..., http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins, http://linkedlifedata.com/resource/pubmed/chemical/Receptors, TNF-Related..., http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Tumor Necrosis Factor, http://linkedlifedata.com/resource/pubmed/chemical/TNF-Related Apoptosis-Inducing..., http://linkedlifedata.com/resource/pubmed/chemical/TNFRSF10A protein, human, http://linkedlifedata.com/resource/pubmed/chemical/TNFRSF10C protein, human, http://linkedlifedata.com/resource/pubmed/chemical/TNFSF10 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor Decoy..., http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
60
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
553-9
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed-meshheading:10676636-Apoptosis, pubmed-meshheading:10676636-Apoptosis Regulatory Proteins, pubmed-meshheading:10676636-CASP8 and FADD-Like Apoptosis Regulating Protein, pubmed-meshheading:10676636-Carrier Proteins, pubmed-meshheading:10676636-Caspase 8, pubmed-meshheading:10676636-Caspase 9, pubmed-meshheading:10676636-Caspases, pubmed-meshheading:10676636-Cells, Cultured, pubmed-meshheading:10676636-Cycloheximide, pubmed-meshheading:10676636-GPI-Linked Proteins, pubmed-meshheading:10676636-Humans, pubmed-meshheading:10676636-Intracellular Signaling Peptides and Proteins, pubmed-meshheading:10676636-Keratinocytes, pubmed-meshheading:10676636-Membrane Glycoproteins, pubmed-meshheading:10676636-Receptors, TNF-Related Apoptosis-Inducing Ligand, pubmed-meshheading:10676636-Receptors, Tumor Necrosis Factor, pubmed-meshheading:10676636-TNF-Related Apoptosis-Inducing Ligand, pubmed-meshheading:10676636-Tumor Necrosis Factor Decoy Receptors, pubmed-meshheading:10676636-Tumor Necrosis Factor-alpha
pubmed:year
2000
pubmed:articleTitle
Regulation of tumor necrosis factor-related apoptosis-inducing ligand sensitivity in primary and transformed human keratinocytes.
pubmed:affiliation
Department of Dermatology, University of Würzburg Medical School, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't