Desferrioxamine, an iron chelator, enhances HIF-1α accumulation via cyclooxygenase-2 signaling pathway
- Kyung Jin Woo; Tae-Jin Lee; Jong-Wook Park; Taeg Kyu Kwon
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- 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-1a protein in dose-dependent manners, but hypoxia mimetic
agent cobalt chloride (CoCl2) induced accumulation of HIF-1a protein but not increase of COX-2 expression. DFX-induced increase
of COX-2 expression and HIF-1a 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-1a protein. PD98059 significantly inhibited the induction of
COX-2 protein and accumulation of HIF-1a, suggesting that DFX-induced increase of HIF-1a 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-1a accumulation in human colon cancer cells, providing the evidence that COX-2 plays as a regulator of
HIF-1a accumulation in DFX-treated colon cancer cells. Together, our findings suggest that iron metabolism may regulate stabilization
of HIF-1a protein by modulating cyclooxygenase-2 signaling pathway.
2006 Elsevier Inc. All rights reserved.
Keywords: COX-2; Desferrioxamine; HIF-1a; ERK; Colon cancer
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