S-Space College of Medicine/School of Medicine (의과대학/대학원) Internal Medicine (내과학전공) Journal Papers (저널논문_내과학전공)
Nitric oxide upregulates the cyclooxygenase-2 expression through the cAMP-response element in its promoter in several cancer cell lines
- Park, Seok-Woo; Sung, Myung-Whun; Heo, Dae-Seog; Inoue, Hiroyasu; Shim, Seon-Hui; Kim, Kwang-Hyun
- Issue Date
- Nature Publishing Group
- Oncogene. 2005 Oct 6;24(44):6689-98.
- Activating Transcription Factor 2; Base Sequence; Cell Line, Tumor; Cyclic AMP Response Element-Binding Protein/physiology; Cyclic GMP/physiology; Cyclooxygenase 2; DNA Primers; Enzyme Activation; Enzyme Inhibitors/pharmacology; Humans; JNK Mitogen-Activated Protein Kinases/metabolism; Membrane Proteins; Nitric Oxide/*physiology; Nitric Oxide Synthase/antagonists & inhibitors; *Promoter Regions, Genetic; Prostaglandin-Endoperoxide Synthases/*genetics; Proto-Oncogene Proteins c-jun/drug effects/physiology; Transcription Factors/drug effects/*physiology; Up-Regulation/*physiology; p38 Mitogen-Activated Protein Kinases/metabolism
- We previously showed that nitric oxide (NO) induces overexpression of cyclooxygenase-2 (COX-2) and production of prostaglandin E(2) in cancer cells. Here, we investigated the mechanisms by which NO induces COX-2 expression in cancer cells. We found that the cAMP-response element (CRE) is a critical factor in NO-induced COX-2 expression in all cells tested. We found that in cancer cells, three transcription factors (TFs) - cAMP response element-binding protein (CREB), activating transcription factor-2 (ATF-2) and c-jun, bound the CRE in the COX-2 promoter, and their activities were increased by addition of the NO donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP). NO-induced activation of soluble guanylate cyclase (sGC), p38 and c-Jun NH(2)-terminal kinase (JNK) upregulated the three TFs, leading to COX-2 overexpression. Addition of dibutyryl-cGMP (db-cGMP) induced COX-2 expression in a manner similar to SNAP; this induction was blocked by a p38 inhibitor (SB202190), but not by a JNK inhibitor (SP600125). NO-induced cGMP was found to activate CREB and ATF-2 in a p38, but not c-jun-dependent manner, while NO induced JNK in a cGMP-independent manner, leading to subsequent activation of c-jun and ATF-2. These results suggest that the low concentrations of endogenous NO present in cancer cell may induce the expression of many genes, including COX-2, which promotes the growth and survival of tumor cells.
- 0950-9232 (Print)
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