Abstract
Development of resistance to TNF-related apoptosis-inducing ligand (TRAIL) in tumor cells is one of the important problems in cancer treatment. Despite the previous report demonstrating that oligomycin suppressed TNF-induced apoptosis, in our screening of small molecules enhancing cancer cell death to TRAIL, oligomycin A (OMA) was found to enhance TRAIL-induced apoptosis in HeLa cells. CCAAT/enhancer-binding protein homologous protein (CHOP) was found to directly bind to death receptor 5 (DR5) promoter through endoplasmic reticulum stress (ER-stress) signaling and sensitize the cells to TRAIL. Among ER-stress associated proteins, OMA triggered the inositol-requiring enzyme 1 (IRE1) signaling pathway, leading to X-binding protein 1 (XBP1) splicing, CHOP expression and DR5 upregulation. In contrast, small-interfering RNA (siRNA) of CHOP reduced the number of apoptotic cells in response to the co-treatment of TRAIL and OMA. Collectively, our data suggest that OMA enhances apoptotic death of cervical cancer cells to TRAIL through upregulation of CHOP-mediated DR5 expression following ER-stress.
Copyright © 2011 Wiley Periodicals, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Endoplasmic Reticulum Stress
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Endoribonucleases / metabolism
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HeLa Cells / drug effects
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Humans
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Mitochondria / drug effects
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Oligomycins / pharmacology*
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Promoter Regions, Genetic / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Splicing
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RNA, Small Interfering / genetics
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
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Regulatory Factor X Transcription Factors
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Signal Transduction / drug effects
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TNF-Related Apoptosis-Inducing Ligand / metabolism*
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TNF-Related Apoptosis-Inducing Ligand / pharmacology
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Transcription Factor CHOP / genetics
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Transcription Factor CHOP / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Up-Regulation / drug effects
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X-Box Binding Protein 1
Substances
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DDIT3 protein, human
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DNA-Binding Proteins
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Oligomycins
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RNA, Small Interfering
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Regulatory Factor X Transcription Factors
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Transcription Factors
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X-Box Binding Protein 1
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XBP1 protein, human
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oligomycin A
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Transcription Factor CHOP
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ERN1 protein, human
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Protein Serine-Threonine Kinases
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Endoribonucleases