Desferrioxamine, an iron chelator, enhances HIF-1{alpha} accumulation via cyclooxygenase-2 signaling pathway
- 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 (Korea, Republic of)
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-1{alpha} protein in dose-dependent manners, but hypoxia mimetic agent cobalt chloride (CoCl{sub 2}) induced accumulation of HIF-1{alpha} protein but not increase of COX-2 expression. DFX-induced increase of COX-2 expression and HIF-1{alpha} 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-1{alpha} protein. PD98059 significantly inhibited the induction of COX-2 protein and accumulation of HIF-1{alpha}, suggesting that DFX-induced increase of HIF-1{alpha} 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-1{alpha} accumulation in human colon cancer cells, providing the evidence that COX-2 plays as a regulator of HIF-1{alpha} accumulation in DFX-treated colon cancer cells. Together, our findings suggest that iron metabolism may regulate stabilization of HIF-1{alpha} protein by modulating cyclooxygenase-2 signaling pathway.
- OSTI ID:
- 20798916
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 343, Issue 1; Other Information: DOI: 10.1016/j.bbrc.2006.02.116; PII: S0006-291X(06)00404-9; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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