Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention

Biochem Pharmacol. 2004 Sep 15;68(6):1089-100. doi: 10.1016/j.bcp.2004.05.031.


Expression of cyclooxygenase-2 (COX-2) has been reported to be elevated in human colorectal adenocarcinoma and other tumors, including those of breast, cervical, prostate, and lung. Genetic knock-out or pharmacological inhibition of COX-2 has been shown to protect against experimentally-induced carcinogenesis. Results from epidemiological and laboratory studies indicate that regular intake of selective COX-2 inhibitors reduces the risk of several forms of human malignancies. Thus, it is conceivable that targeted inhibition of abnormally or improperly elevated COX-2 provides one of the most effective and promising strategies for cancer chemoprevention. The COX-2 promoter contains a TATA box and binding sites for several transcription factors including nuclear factor-kappaB (NF-kappaB), nuclear factor for interleukin-6/CCAAT enhancer-binding protein (NF-IL6/C/EBP) and cyclic AMP response element (CRE) binding protein. Upregulation of COX-2 is mediated by a variety of stimuli including tumor promoters, oncogenes, and growth factors. Stimulation of either protein kinase C (PKC) or Ras signaling enhances mitogen-activated protein kinase (MAPK) activity, which, in turn, activates transcription of cox-2. Celecoxib, the first US FDA approved selective COX-2 inhibitor, initially developed for the treatment of adult rheumatoid arthritis and osteoarthritis, has been reported to reduce the formation of polyps in patients with familial adenomatous polyposis. This COX-2 specific inhibitor also protects against experimentally-induced carcinogenesis, but the underlying molecular mechanisms are poorly understood. The present review covers the signal transduction pathways responsible for regulating COX-2 expression as novel molecular targets of chemopreventive agents with celecoxib as a specific example.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Celecoxib
  • Chemoprevention
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology*
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Membrane Proteins
  • Neoplasms / prevention & control
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Pyrazoles
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use
  • Transcription, Genetic / drug effects


  • Antineoplastic Agents
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Membrane Proteins
  • Pyrazoles
  • Sulfonamides
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Celecoxib