Abstract
Potent selective cyclooxygenase-2 (COX-2) inhibitors are effective in controlling inflammatory disorders but are associated with cardiovascular complications. Their clinical use has been severely limited. We propose that transcription-based inhibition of COX-2 expression represents a therapeutic strategy that may circumvent the undesired complications of COX-2 inhibitors. Reported data from several laboratories including ours have identified C/EBPbeta as a key transactivator mediating COX-2 transcriptional activation induced by diverse pro-inflammatory mediators. Results from our recent work show that sodium salicylate at pharmacological concentrations inhibits C/EBPbeta binding to COX-2 promoter by direct inhibition of p90 ribosomal S6 kinase (RSK). RSK phosphorylates C/EBPbeta and stimulates its binding to enhancer elements. We propose that RSK1/2 is a potential target for screening drugs with novel anti-inflammatory and anti-neoplastic therapeutic potentials.
Publication types
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Research Support, N.I.H., Extramural
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Review
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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CCAAT-Enhancer-Binding Protein-beta / genetics
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CCAAT-Enhancer-Binding Protein-beta / metabolism
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism*
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism*
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Gene Expression Regulation, Enzymologic / drug effects
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Genetic Therapy / trends
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Humans
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Inflammation / drug therapy
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Inflammation / genetics
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Inflammation / metabolism*
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Phosphorylation
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Promoter Regions, Genetic / genetics
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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RNA Interference
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors
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Salicylates / pharmacology
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Transcription, Genetic*
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Transcriptional Activation
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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CCAAT-Enhancer-Binding Protein-beta
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Protein Kinase Inhibitors
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RNA, Small Interfering
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Salicylates
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Cyclooxygenase 2
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Ribosomal Protein S6 Kinases, 90-kDa