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

被引:335
作者
Chun, KS [1 ]
Surh, YJ [1 ]
机构
[1] Seoul Natl Univ, Coll Pharm, Lab Biochem & Mol Toxicol, Seoul 151742, South Korea
关键词
cyclooxygenase-2; celecoxib; transcription factors; mitogen-activated protein kinase; chemoprevention;
D O I
10.1016/j.bcp.2004.05.031
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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. (C) 2004 Elsevier Inc. All rights reserved.
引用
收藏
页码:1089 / 1100
页数:12
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