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Nitric oxide upregulates the cyclooxygenase-2 expression through the cAMP-response element in its promoter in several cancer cell lines

Cited 41 time in Web of Science Cited 43 time in Scopus
Authors
Park, Seok-Woo; Sung, Myung-Whun; Heo, Dae-Seog; Inoue, Hiroyasu; Shim, Seon-Hui; Kim, Kwang-Hyun
Issue Date
2005-07-12
Publisher
Nature Publishing Group
Citation
Oncogene. 2005 Oct 6;24(44):6689-98.
Keywords
Activating Transcription Factor 2Base SequenceCell Line, TumorCyclic AMP Response Element-Binding Protein/physiologyCyclic GMP/physiologyCyclooxygenase 2DNA PrimersEnzyme ActivationEnzyme Inhibitors/pharmacologyHumansJNK Mitogen-Activated Protein Kinases/metabolismMembrane ProteinsNitric Oxide/*physiologyNitric Oxide Synthase/antagonists & inhibitors*Promoter Regions, GeneticProstaglandin-Endoperoxide Synthases/*geneticsProto-Oncogene Proteins c-jun/drug effects/physiologyTranscription Factors/drug effects/*physiologyUp-Regulation/*physiologyp38 Mitogen-Activated Protein Kinases/metabolism
Abstract
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.
ISSN
0950-9232 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16007171

http://hdl.handle.net/10371/15998
DOI
https://doi.org/10.1038/sj.onc.1208816
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College of Medicine/School of Medicine (의과대학/대학원)Otorhinolaryngology (이비인후과학전공)Journal Papers (저널논문_이비인후과학전공)
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