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Desferrioxamine, an iron chelator, enhances HIF-1alpha accumulation via cyclooxygenase-2 signaling pathway.
Biochem Biophys Res Commun. 2006 Apr 28; 343(1):8-14.BB

Abstract

Cyclooxygenase-2 (COX-2) is an important inducible enzyme in inflammation and is overexpressed in a variety of cancers. Evidence is rapidly accumulating that chronic inflammation may contribute to carcinogenesis through increase of cell proliferation, angiogenesis, and metastasis in a number of neoplasms, including colorectal carcinoma. In the present study, we investigated some mechanistic aspects of DFX-induced hypoxia-driven COX-2 expression. Desferrioxamine (DFX), an iron chelator, is known to upregulate inflammatory mediators. DFX induced the expression of COX-2 and accumulation of HIF-1alpha protein in dose-dependent manners, but hypoxia mimetic agent cobalt chloride (CoCl2) induced accumulation of HIF-1alpha protein but not increase of COX-2 expression. DFX-induced increase of COX-2 expression and HIF-1alpha protein level was attenuated by addition of ferric citrate. This result suggested that the iron chelating function of DFX was important to induce the increase of COX-2 and HIF-1alpha protein. PD98059 significantly inhibited the induction of COX-2 protein and accumulation of HIF-1alpha, suggesting that DFX-induced increase of HIF-1alpha and COX-2 protein was mediated, at least in part, through the ERK signaling pathway. In addition, pretreatment with NS-398 to inhibit COX-2 activity also effectively suppressed DFX-induced HIF-1alpha accumulation in human colon cancer cells, providing the evidence that COX-2 plays as a regulator of HIF-1alpha accumulation in DFX-treated colon cancer cells. Together, our findings suggest that iron metabolism may regulate stabilization of HIF-1alpha protein by modulating cyclooxygenase-2 signaling pathway.

Authors+Show Affiliations

Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16527254

Citation

Woo, Kyung Jin, et al. "Desferrioxamine, an Iron Chelator, Enhances HIF-1alpha Accumulation Via Cyclooxygenase-2 Signaling Pathway." Biochemical and Biophysical Research Communications, vol. 343, no. 1, 2006, pp. 8-14.
Woo KJ, Lee TJ, Park JW, et al. Desferrioxamine, an iron chelator, enhances HIF-1alpha accumulation via cyclooxygenase-2 signaling pathway. Biochem Biophys Res Commun. 2006;343(1):8-14.
Woo, K. J., Lee, T. J., Park, J. W., & Kwon, T. K. (2006). Desferrioxamine, an iron chelator, enhances HIF-1alpha accumulation via cyclooxygenase-2 signaling pathway. Biochemical and Biophysical Research Communications, 343(1), 8-14.
Woo KJ, et al. Desferrioxamine, an Iron Chelator, Enhances HIF-1alpha Accumulation Via Cyclooxygenase-2 Signaling Pathway. Biochem Biophys Res Commun. 2006 Apr 28;343(1):8-14. PubMed PMID: 16527254.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Desferrioxamine, an iron chelator, enhances HIF-1alpha accumulation via cyclooxygenase-2 signaling pathway. AU - Woo,Kyung Jin, AU - Lee,Tae-Jin, AU - Park,Jong-Wook, AU - Kwon,Taeg Kyu, Y1 - 2006/02/28/ PY - 2006/02/16/received PY - 2006/02/17/accepted PY - 2006/3/11/pubmed PY - 2006/5/25/medline PY - 2006/3/11/entrez SP - 8 EP - 14 JF - Biochemical and biophysical research communications JO - Biochem Biophys Res Commun VL - 343 IS - 1 N2 - Cyclooxygenase-2 (COX-2) is an important inducible enzyme in inflammation and is overexpressed in a variety of cancers. Evidence is rapidly accumulating that chronic inflammation may contribute to carcinogenesis through increase of cell proliferation, angiogenesis, and metastasis in a number of neoplasms, including colorectal carcinoma. In the present study, we investigated some mechanistic aspects of DFX-induced hypoxia-driven COX-2 expression. Desferrioxamine (DFX), an iron chelator, is known to upregulate inflammatory mediators. DFX induced the expression of COX-2 and accumulation of HIF-1alpha protein in dose-dependent manners, but hypoxia mimetic agent cobalt chloride (CoCl2) induced accumulation of HIF-1alpha protein but not increase of COX-2 expression. DFX-induced increase of COX-2 expression and HIF-1alpha protein level was attenuated by addition of ferric citrate. This result suggested that the iron chelating function of DFX was important to induce the increase of COX-2 and HIF-1alpha protein. PD98059 significantly inhibited the induction of COX-2 protein and accumulation of HIF-1alpha, suggesting that DFX-induced increase of HIF-1alpha and COX-2 protein was mediated, at least in part, through the ERK signaling pathway. In addition, pretreatment with NS-398 to inhibit COX-2 activity also effectively suppressed DFX-induced HIF-1alpha accumulation in human colon cancer cells, providing the evidence that COX-2 plays as a regulator of HIF-1alpha accumulation in DFX-treated colon cancer cells. Together, our findings suggest that iron metabolism may regulate stabilization of HIF-1alpha protein by modulating cyclooxygenase-2 signaling pathway. SN - 0006-291X UR - https://www.unboundmedicine.com/medline/citation/16527254/Desferrioxamine_an_iron_chelator_enhances_HIF_1alpha_accumulation_via_cyclooxygenase_2_signaling_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(06)00404-9 DB - PRIME DP - Unbound Medicine ER -