Abstract
Proteasome inhibitors are known to induce apoptosis in a variety of cancer cells. On the other hand, maspin, a non-inhibitory serine protease inhibitor, is shown to sensitize cancer cells to therapeutic agents that induce apoptosis. We examined the consequence of maspin expression in prostate cancer cells targeted for treatment with various proteasome inhibitors. We observed that proteasome inhibitors induced apoptosis more effectively in maspin transfected human prostate cancer DU145 cells than in control cells. Interestingly, increased apoptosis in these cells was associated with a significant induction of maspin expression. MG-132, a proteasome inhibitor, induced endogenous and ectopic [cytomegalovirus promoter (CMV)-driven] maspin expression, and maspin siRNA attenuated MG-132-induced apoptosis. Proteasome inhibitor-induced maspin expression was inhibited by actinomycin D (Act D) and cyclohexamide (CHX), and by the inhibitors of p38MAPK, but not ERK1/2 or NF-kappaB. Electrophoretic mobility-shift assay (EMSA) and promoter-reporter activity analyses suggested that p38MAPK activated transcription factor AP-1 is responsible for proteasome inhibitor-induced maspin expression. Taken together, these observations demonstrate that proteasome inhibitors induce maspin expression by activating p38MAPK pathway, and that maspin thus expressed, in turn, augments proteasome inhibitor-induced apoptosis in prostate cancer cells. Our results suggest that gene therapy involving ectopic maspin expression may dramatically improve the efficacy of proteasome inhibitors for the treatment of prostate cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects*
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Cell Line, Tumor
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Cysteine Proteinase Inhibitors / pharmacology*
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Cysteine Proteinase Inhibitors / therapeutic use
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Cytomegalovirus / drug effects
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Cytomegalovirus / genetics
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Dose-Response Relationship, Drug
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Genetic Vectors / drug effects
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Humans
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Imidazoles / pharmacology
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Leupeptins / pharmacology
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Luteolin / pharmacology
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Male
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Phosphorylation
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Promoter Regions, Genetic / drug effects
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / enzymology
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors*
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Protein Kinase Inhibitors / pharmacology
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Pyridines / pharmacology
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RNA Interference
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RNA, Messenger / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Serpins / genetics
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Serpins / metabolism*
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Transcription Factor AP-1 / metabolism
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Transcription, Genetic / drug effects*
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Transfection
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Antineoplastic Agents
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Cysteine Proteinase Inhibitors
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Imidazoles
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Leupeptins
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Proteasome Inhibitors
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Protein Kinase Inhibitors
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Pyridines
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RNA, Messenger
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RNA, Small Interfering
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SERPIN-B5
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Serpins
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Transcription Factor AP-1
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p38 Mitogen-Activated Protein Kinases
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Proteasome Endopeptidase Complex
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Luteolin
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SB 203580
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde