Linked Life Data

17659339

Source:http://linkedlifedata.com/resource/pubmed/id/17659339

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2008-2-15
pubmed:abstractText
The Hodgkin cells and Reed-Sternberg cells (HRS) of classical Hodgkin lymphoma (CHL) are derived from germinal center B cells. The pathogenesis of CHL is unclear but constitutive activation of NFkappaB may contribute. Proteasome inhibition aimed at inhibiting NFkappaB has been shown to result in apoptosis in HRS cells. Here we investigated the effects of bortezomib, a proteasome inhibitor, in HRS cells with a combination of functional assays and gene expression profiling (GEP). Exposure of KMH2 and L428 cells to bortezomib resulted in inhibition of proliferation and induction of apoptosis. Gene expression analysis of KMH2 cells by oligonucleotide cDNA microarrays showed that a limited set of genes were differentially expressed involving several key cellular pathways including cell cycle and apoptosis. Among them, the caspase 8 inhibitor cFLIP was down-regulated and confirmed by Q-PCR. Given the evidence that cFLIP in HRS cells contribute to cells' insensitive to death receptor-mediated apoptosis, we combined bortezomib and TRAIL. This combination caused further down-regulation of cFLIP protein and increased apoptosis in CHL cells demonstrated by PARP p85 immunohistochemistry and immunoblotting. Such apoptotic effects were inhibited by caspase inhibitor z-VAD-FMK, confirming the pro-apoptotic effects of bortezomib and TRAIL are caspase-dependent. Bortezomib has no detectable effect on expression of TRAIL receptor DR4/DR5 in these two cell lines. Tissue microarray analysis of primary Hodgkin lymphomas displayed that 82% cases (95/116) expressed cFLIP in Reed-Sternberg cells. The discovery of apoptotic pathways that can be manipulated by proteasome inhibition provides rationale for the combination of bortezomib and agents such as TRAIL in CHL treatment.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0145-2126
pubmed:author
pubmed:issnType
Print
pubmed:volume
32
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
275-85
pubmed:meshHeading
pubmed-meshheading:17659339-Antineoplastic Agents, pubmed-meshheading:17659339-Apoptosis, pubmed-meshheading:17659339-Blotting, Western, pubmed-meshheading:17659339-Boronic Acids, pubmed-meshheading:17659339-CASP8 and FADD-Like Apoptosis Regulating Protein, pubmed-meshheading:17659339-Caspases, pubmed-meshheading:17659339-Cell Line, Tumor, pubmed-meshheading:17659339-Cell Proliferation, pubmed-meshheading:17659339-Flow Cytometry, pubmed-meshheading:17659339-Gene Expression, pubmed-meshheading:17659339-Gene Expression Profiling, pubmed-meshheading:17659339-Hodgkin Disease, pubmed-meshheading:17659339-Humans, pubmed-meshheading:17659339-Immunohistochemistry, pubmed-meshheading:17659339-Oligonucleotide Array Sequence Analysis, pubmed-meshheading:17659339-Pyrazines, pubmed-meshheading:17659339-Reed-Sternberg Cells, pubmed-meshheading:17659339-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:17659339-TNF-Related Apoptosis-Inducing Ligand, pubmed-meshheading:17659339-Tissue Array Analysis
pubmed:year
2008
pubmed:articleTitle
Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies.
pubmed:affiliation
Department of Clinical Pathology, United States.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't