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/EBPβ 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/EBPβ
binding to COX-2 promoter by direct inhibition of p90 ribosomal S6 kinase (RSK). RSK
phosphorylates C/EBPβ 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.
Keywords
Cyclooxygenase-2 - inflammation - C/EBPβ,aspirin - P90 ribosomal S6 kinase