Abstract
Simvastatin (SVA) was shown to up-regulate expression of death receptor-5 (DR5), CCAAT/enhancer binding protein homologous protein (CHOP) and phosphorylated c-Jun N-terminal kinase (pJNK) in human breast cancer cell lines. siRNA knockdown of DR5, CHOP or JNK significantly blocked SVA-induced apoptosis, demonstrating the importance of JNK/CHOP/DR5 signaling pathway in SVA-induced apoptosis. Exogenous addition of either mevalonate or geranylgeranyl pyrophosphate (GGPP) inhibited SVA activation of JNK/CHOP/DR5 pro-apoptotic pathway, indicating that activation of JNK/CHOP/DR5 pro-apoptotic pathway is dependent on SVA inhibition of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase and its intermediate GGPP. Data provide novel insight into better understanding the anticancer mechanisms of SVA.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Female
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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MAP Kinase Signaling System / drug effects*
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Mevalonic Acid / metabolism
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Polyisoprenyl Phosphates / pharmacology
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RNA, Small Interfering
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Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
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Sesquiterpenes / pharmacology
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Signal Transduction / drug effects
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Simvastatin / pharmacology*
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Transcription Factor CHOP / genetics
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Transcription Factor CHOP / metabolism*
Substances
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Antineoplastic Agents
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DDIT3 protein, human
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Polyisoprenyl Phosphates
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RNA, Small Interfering
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Sesquiterpenes
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Transcription Factor CHOP
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farnesyl pyrophosphate
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Simvastatin
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JNK Mitogen-Activated Protein Kinases
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geranylgeranyl pyrophosphate
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Mevalonic Acid