Desferrioxamine, an iron chelator, enhances HIF-1alpha accumulation via cyclooxygenase-2 signaling pathway.

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: Kyung Jin Woo, Tae-Jin Lee, Jong-Wook Park, Taeg Kyu Kwon
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 343 Issue 1 Pg. 8-14 (Apr 28 2006) ISSN: 0006-291X [Print] United States
• PMID: 16527254 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclooxygenase 2 Inhibitors
• Ferric Compounds
• Flavonoids
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Iron Chelating Agents
• Tumor Suppressor Protein p53
• ferric citrate
• Cyclooxygenase 2
• Mitogen-Activated Protein Kinases
• Deferoxamine
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Colonic Neoplasms (metabolism)
• Cyclooxygenase 2 (drug effects, metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Deferoxamine (pharmacology)
• Ferric Compounds (pharmacology)
• Flavonoids (pharmacology)
• Humans
• Hypoxia (chemically induced, metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, metabolism)
• Iron Chelating Agents (pharmacology)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Signal Transduction
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (metabolism)