Abstract
Iron deficiency affects 500 million people, yet the molecular role of iron in gene expression remains poorly characterized. In addition, the alterations in global gene expression after iron chelation remain unclear and are important to assess for understanding the molecular pathology of iron deficiency and the biological effects of chelators. Considering this, we assessed the effect on whole genome gene expression of two iron chelators (desferrioxamine and 2-hydroxy-1-napthylaldehyde isonicotinoyl hydrazone) that have markedly different permeability properties. Sixteen genes were significantly regulated by both ligands, whereas a further 50 genes were significantly regulated by either compound. Apart from iron-mediated regulation of expression via hypoxia inducible factor-1α, it was noteworthy that the transcription factor p53 was also involved in iron-regulated gene expression. Examining 16 genes regulated by both chelators in normal and neoplastic cells, five genes (APP, GDF15, CITED2, EGR1, and PNRC1) were significantly differentially expressed between the cell types. In view of their functions in tumor suppression, proliferation, and apoptosis, these findings are important for understanding the selective antiproliferative effects of chelators against neoplastic cells. Most of the genes identified have not been described previously to be iron-regulated and are important for understanding the molecular and cellular effects of iron depletion.
Footnotes
This work was supported by the National Health and Medical Research Council of Australia [Grant 570952 and Senior Principal Research Fellowship]; the Australian Research Council [Grant DP0773027]; the Prostate Cancer Foundation; and the Cancer Institute New South Wales.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.109.061028
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ABBREVIATIONS:
- 311
- 2-hydroxy-1-napthylaldehyde isonicotinoyl hydrazone
- DFO
- desferrioxamine
- IRP
- iron-regulatory protein
- IRE
- iron-responsive element
- UTR
- untranslated region
- HIF-1
- hypoxia-inducible factor-1
- HUVEC
- human umbilical vein endothelial cell
- MEF
- murine embryonic fibroblast
- Tet
- tetracycline
- RT
- reverse transcription
- PCR
- polymerase chain reaction
- Dp44mT
- di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone
- APP
- amyloid β (A4) precursor protein
- GDF15
- growth differentiation factor 15
- FAC
- ferric ammonium citrate
- CON
- control medium alone
- TfR1
- transferrin receptor 1
- BNIP3
- BCL2/adenovirus E1B 19-kDa interacting protein 3
- CITED2
- Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxyl-terminal domain, 2
- EGR1
- early growth response 1
- ERO1L
- ERO1-like
- GDF15
- growth differentiation factor 15
- NDRG-1
- N-myc downstream regulated gene 1
- PNRC1
- proline-rich nuclear receptor coactivator 1
- PPM1D
- protein phosphatase 1D magnesium-dependent, 32 δ isoform.
- Received September 18, 2009.
- Accepted December 18, 2009.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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