Abstract
The flavonoid quercetin 3-glucoside (Q3G) protected SH-SY5Y, HEK293, and MCF-7 cells against hydrogen peroxide-induced oxidative stress. cDNA microarray studies suggested that Q3G-pretreated cells subjected to oxidative stress up-regulate the expression of genes associated with lipid and cholesterol biosynthesis. Q3G pretreatment elevated both the expression and activation of sterol regulatory element-binding protein-2 (SREBP-2) only in SH-SY5Y cells subjected to oxidative stress. Inhibition of SREBP-2 expression by small interfering RNA or small molecule inhibitors of 2,3-oxidosqualene:lanosterol cyclase or HMG-CoA reductase blocked Q3G-mediated cytoprotection in SH-SY5Y cells. By contrast, Q3G did not protect either HEK293 or MCF-7 cells via this signaling pathway. Moreover, the addition of isopentenyl pyrophosphate rescued SH-SY5Y cells from the inhibitory effect of HMG-CoA reductase inhibition. Last, Q3G pretreatment enhanced the incorporation of [(14)C]acetate into [(14)C]cholesterol in SH-SY5Y cells under oxidative stress. Taken together, these studies suggest a novel mechanism for flavonoid-induced cytoprotection in SH-SY5Y cells involving SREBP-2-mediated sterol synthesis that decreases lipid peroxidation by maintaining membrane integrity in the presence of oxidative stress.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor
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Cell Membrane / genetics
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Cell Membrane / metabolism
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Cell Membrane / pathology
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Cholesterol / biosynthesis
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics
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Hemiterpenes / pharmacology
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Humans
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Hydrogen Peroxide / pharmacology
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Hydroxymethylglutaryl CoA Reductases / metabolism
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
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Intramolecular Transferases / antagonists & inhibitors
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Intramolecular Transferases / metabolism
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Lipid Metabolism / drug effects*
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Lipid Metabolism / genetics
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Lipid Peroxidation / drug effects
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Lipid Peroxidation / genetics
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Neuroblastoma / genetics
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Neuroblastoma / metabolism*
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Neuroblastoma / pathology
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Oligonucleotide Array Sequence Analysis
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Organophosphorus Compounds / pharmacology
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Oxidative Stress / drug effects*
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Quercetin / analogs & derivatives*
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Quercetin / pharmacology
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RNA, Small Interfering / genetics
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Sterol Regulatory Element Binding Protein 2 / antagonists & inhibitors
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Sterol Regulatory Element Binding Protein 2 / genetics
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Sterol Regulatory Element Binding Protein 2 / metabolism*
Substances
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Hemiterpenes
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Neoplasm Proteins
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Organophosphorus Compounds
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RNA, Small Interfering
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SREBF2 protein, human
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Sterol Regulatory Element Binding Protein 2
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isoquercitrin
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isopentenyl pyrophosphate
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Cholesterol
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Quercetin
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Hydrogen Peroxide
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Hydroxymethylglutaryl CoA Reductases
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Intramolecular Transferases
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lanosterol synthase
Associated data
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GEO/GSE6199
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GEO/GSE6200
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GEO/GSM143163
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GEO/GSM143243
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GEO/GSM143247
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GEO/GSM143248
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GEO/GSM143249
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GEO/GSM143250
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GEO/GSM143251
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GEO/GSM143252
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GEO/GSM143253
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GEO/GSM143254
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GEO/GSM143255
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GEO/GSM143256
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GEO/GSM143257
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GEO/GSM143258
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GEO/GSM143259
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GEO/GSM143260