Source:http://linkedlifedata.com/resource/pubmed/id/20555361
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
8
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| pubmed:dateCreated |
2010-8-12
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| pubmed:abstractText |
Bortezomib is an effective agent for treating multiple myeloma (MM). To investigate the underlying mechanisms associated with acquired resistance to this agent, we established two bortezomib-resistant MM cell lines, KMS-11/BTZ and OPM-2/BTZ, the 50% inhibitory concentration values of which were respectively 24.7- and 16.6-fold higher than their parental cell lines. No activation of caspase and BH3-only proteins such as Noxa was noted in bortezomib-resistant cells after exposure to the drug. The accumulation of polyubiquitinated proteins was reduced in bortezomib-resistant cells compared with the parental cells, associated with avoidance of catastrophic ER stress as assessed by downregulation of CHOP expression. These resistant MM cells have a unique point mutation, G322A, in the gene encoding the proteasome beta5 subunit (PSMB5), likely resulting in conformational changes to the bortezomib-binding pocket of this subunit. KMS-11 parental cells transfected to express mutated PSMB5 also showed reduced bortezomib-induced apoptosis compared with those expressing wild-type PSMB5 or the parental cells. Expression of mutated PSMB5 was associated with the prevention of the accumulation of unfolded proteins. Thus, a fraction of MM cells may acquire bortezomib resistance by suppressing apoptotic signals through the inhibition of unfolded protein accumulation and subsequent excessive ER stress by a mutation of the PSMB5 gene.
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| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Boronic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/DNA Primers,
http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/PSMB5 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrazines,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin,
http://linkedlifedata.com/resource/pubmed/chemical/bortezomib
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| pubmed:status |
MEDLINE
|
| pubmed:month |
Aug
|
| pubmed:issn |
1476-5551
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| pubmed:author | |
| pubmed:issnType |
Electronic
|
| pubmed:volume |
24
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1506-12
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| pubmed:meshHeading |
pubmed-meshheading:20555361-Antineoplastic Agents,
pubmed-meshheading:20555361-Apoptosis,
pubmed-meshheading:20555361-Base Sequence,
pubmed-meshheading:20555361-Boronic Acids,
pubmed-meshheading:20555361-Cell Line, Tumor,
pubmed-meshheading:20555361-Cell Proliferation,
pubmed-meshheading:20555361-DNA Primers,
pubmed-meshheading:20555361-Drug Resistance, Neoplasm,
pubmed-meshheading:20555361-Endoplasmic Reticulum,
pubmed-meshheading:20555361-Humans,
pubmed-meshheading:20555361-Multiple Myeloma,
pubmed-meshheading:20555361-Mutation,
pubmed-meshheading:20555361-Neoplasm Proteins,
pubmed-meshheading:20555361-Point Mutation,
pubmed-meshheading:20555361-Proteasome Endopeptidase Complex,
pubmed-meshheading:20555361-Protein Denaturation,
pubmed-meshheading:20555361-Pyrazines,
pubmed-meshheading:20555361-Ubiquitin
|
| pubmed:year |
2010
|
| pubmed:articleTitle |
Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress.
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| pubmed:affiliation |
Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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