Abstract
The novel proteasome inhibitor NPI-0052 has been shown to sensitize tumor cells to apoptosis by various chemotherapeutic drugs and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), although the mechanisms involved are not clear. We hypothesized that NPI-0052-mediated sensitization may result from NF-kappaB inhibition and downstream modulation of the metastasis inducer Snail and the metastasis suppressor/immunosurveillance cancer gene product Raf-1 kinase inhibitory protein (RKIP). Human prostate cancer cell lines were used as models, as they express different levels of these proteins. We show that NPI-0052 inhibits both NF-kappaB and Snail and induces RKIP expression, thus resulting in cell sensitization to CDDP and TRAIL. The direct role of NF-kappaB inhibition in sensitization was corroborated with the NF-kappaB inhibitor DHMEQ, which mimicked NPI-0052 in sensitization and inhibition of Snail and induction of RKIP. The direct role of Snail inhibition by NPI-0052 in sensitization was shown with Snail small interfering RNA, which reversed resistance and induced RKIP. Likewise, the direct role of RKIP induction in sensitization was revealed by both overexpression of RKIP (mimicking NPI-0052) and RKIP small interfering RNA that inhibited NPI-0052-mediated sensitization. These findings show that NPI-0052 modifies the NF-kappaB-Snail-RKIP circuitry in tumor cells and results in downstream inhibition of antiapoptotic gene products and chemoimmunosensitization. The findings also identified Snail and RKIP as targets for reversal of resistance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Blotting, Western
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Boronic Acids / pharmacology
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Bortezomib
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Cisplatin / pharmacology
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Humans
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Lactones / pharmacology*
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Leupeptins / pharmacology
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Male
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Melanoma / drug therapy*
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Melanoma / metabolism
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Melanoma / pathology
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Membrane Potential, Mitochondrial / drug effects
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Phosphatidylethanolamine Binding Protein / genetics
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Phosphatidylethanolamine Binding Protein / metabolism*
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Proteasome Inhibitors
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Proto-Oncogene Proteins c-raf / metabolism
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Pyrazines / pharmacology
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Pyrroles / pharmacology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Snail Family Transcription Factors
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TNF-Related Apoptosis-Inducing Ligand / pharmacology
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transfection
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Boronic Acids
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Lactones
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Leupeptins
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NF-kappa B
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PEBP1 protein, human
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Phosphatidylethanolamine Binding Protein
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Proteasome Inhibitors
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Pyrazines
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Pyrroles
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RNA, Messenger
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RNA, Small Interfering
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Snail Family Transcription Factors
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TNF-Related Apoptosis-Inducing Ligand
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Transcription Factors
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Bortezomib
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marizomib
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Proto-Oncogene Proteins c-raf
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Cisplatin
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde