Abstract
Bortezomib (PS-341), a selective inhibitor of proteasome, induces apoptosis in various tumor cells, but its mechanism of action is unclear. Treatment with PS-341 induces apoptosis in SUDHL6 (DHL6), but not SUDHL4 (DHL4), lymphoma cells. Microarray analysis shows high RNA levels of heat shock protein-27 (Hsp27) in DHL4 versus DHL6 cells, which correlates with Hsp27 protein expression. Blocking Hsp27 using an antisense strategy restores the apoptotic response to PS-341 in DHL4 cells; conversely, ectopic expression of wild-type Hsp27 renders PS-341-sensitive DHL6 cells resistant to PS-341. These findings provide the first evidence that Hsp27 confers PS-341 resistance.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis / drug effects
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Boronic Acids / pharmacology*
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Bortezomib
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Cell Line, Tumor
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Cell Survival / drug effects
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Cysteine Endopeptidases
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Drug Resistance, Neoplasm
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HSP27 Heat-Shock Proteins
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Heat-Shock Proteins*
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Humans
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Leupeptins / pharmacology
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Lymphoma / drug therapy*
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Lymphoma / enzymology
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Lymphoma / genetics
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Lymphoma / pathology
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Molecular Chaperones
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Multienzyme Complexes / antagonists & inhibitors
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Proteasome Endopeptidase Complex
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Pyrazines / pharmacology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Transfection
Substances
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Boronic Acids
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HSP27 Heat-Shock Proteins
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HSPB1 protein, human
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Heat-Shock Proteins
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Leupeptins
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Molecular Chaperones
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Multienzyme Complexes
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Neoplasm Proteins
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Pyrazines
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RNA, Messenger
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Bortezomib
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde