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Glucocorticoid Represses Hypoxia-induced Cyclooxygenase-2 and Hypoxia Inducible Factor-1α Expression through Induction of the Glucocorticoid-induced Leucine Zipper.
MedLine Citation:
PMID:  24172143     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: The cyclooxygenase-2 (COX-2)/ prostaglandin E2 pathway in hypoxic cancer cells has important implications for stimulation of inflammation and tumorigenesis. However, the mechanism of GR inhibition of COX-2 under hypoxia has not been investigated intensively. Here, we explored the mechanisms underlying glucocorticoid inhibition of hypoxia-induced COX-2 in human distal lung epithelial A549 cells.
EXPERIMENTAL APPROACH: The expressions of COX-2 and glucocorticoid-induced leucine zipper (GILZ) in A549 cells were determined by Western blot and/or qRT-PCR, respectively. The anti-invasive effect of GILZ was evaluated on A549 cells using the matrigel invasion assay.
KEY RESULTS: We first observed that hypoxia induced COX-2 protein and mRNA levels and promoter activity were suppressed by dexamethasone and antagonized by the glucocorticoid receptor (GR) antagonist RU486. Second, we demonstrated that overexpression of GILZ inhibited hypoxia-induced COX-2 expression levels and knockdown of GILZ reduced glucocorticoid inhibition of hypoxia-induced COX-2 expression, indicating that dexamethasone inhibition of hypoxia-induced COX-2 is mediated by GILZ. Third, we found that GILZ expression suppresses hypoxia inducible factor (HIF)-1α expression at the protein level, affecting the HIF-1 signaling pathway. Finally, we observed that hypoxia-induced cell invasion is dramatically reduced by GILZ expression. Our results show that dexamethasone induced GILZ not only inhibits the hypoxic induction of COX-2 expression and cell invasion but further blocks the HIF-1 pathway by destabilizing HIF-1α expression.
CONCLUSION AND IMPLICATIONS: Taken together, suppression of hypoxia-induced COX-2 by glucocorticoid is mediated by the GILZ. These results suggest the GILZ is a key therapeutic target for suppression of inflammation under hypoxia.
Authors:
Wonchung Lim; Choa Park; Myeong Kuk Shim; Yonghee Lee; Youmie Lee; Youngjoo Lee
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-10-31
Journal Detail:
Title:  British journal of pharmacology     Volume:  -     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Oct 
Date Detail:
Created Date:  2013-10-31     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
This article is protected by copyright. All rights reserved.
Affiliation:
Department of Bioscience and Biotechnology, College of Life Science, Institute of Biotechnology, Sejong University, Kwangjingu, Kunjadong, Seoul 143-747, Korea.
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