Transcription-based COX-2 inhibition: a therapeutic strategy.
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.
Wu
Kenneth K
KK
Vascular Biology Research Center and Division of Hematology, Department of Medicine, The University of Texas Health Science Center at Houston, Texas 77030, USA. Kenneth.K.Wu@uth.tmc.edu
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015316:Genetic Therapy / Q000639:trends; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors; D012459:Salicylates / Q000494:pharmacology; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D022782:CCAAT-Enhancer-Binding Protein-beta; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D012459:Salicylates; D051546:Cyclooxygenase 2; D038744:Ribosomal Protein S6 Kinases, 90-kDa