Document Detail


Altered iron homeostasis involvement in arsenite-mediated cell transformation.
MedLine Citation:
PMID:  16443159     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chronic exposure to low doses of arsenite causes transformation of human osteogenic sarcoma (HOS) cells. Although oxidative stress is considered important in arsenite-induced cell transformation, the molecular and cellular mechanisms by which arsenite transforms human cells are still unknown. In the present study, we investigated whether altered iron homeostasis, known to affect cellular oxidative stress, can contribute to the arsenite-mediated cell transformation. Using arsenite-induced HOS cell transformation as a model, it was found that total iron levels are significantly higher in transformed HOS cells in comparison to parental control HOS cells. Under normal iron metabolism conditions, iron homeostasis is tightly controlled by inverse regulation of ferritin and transferrin receptor (TfR) through iron regulatory proteins (IRP). Increased iron levels in arsenite transformed cells should theoretically lead to higher ferritin and lower TfR in these cells than in controls. However, the results showed that both ferritin and TfR are decreased, apparently through two different mechanisms. A lower ferritin level in cytoplasm was due to the decreased mRNA in the arsenite-transformed HOS cells, while the decline in TfR was due to a lowered IRP-binding activity. By challenging cells with iron, it was further established that arsenite-transformed HOS cells are less responsive to iron treatment than control HOS cells, which allows accumulation of iron in the transformed cells, as exemplified by significantly lower ferritin induction. On the other hand, caffeic acid phenethyl ester (CAPE), an antioxidant previously shown to suppress As-mediated cell transformation, prevents As-mediated ferritin depletion. In conclusion, our results suggest that altered iron homeostasis contributes to arsenite-induced oxidative stress and, thus, may be involved in arsenite-mediated cell transformation.
Authors:
Jing Wu; Jonathan Eckard; Haobin Chen; Max Costa; Krystyna Frenkel; Xi Huang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2005-11-08
Journal Detail:
Title:  Free radical biology & medicine     Volume:  40     ISSN:  0891-5849     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-01-30     Completed Date:  2006-05-02     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  444-52     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Antioxidants / pharmacology
Arsenites / pharmacology*
Caffeic Acids / pharmacology
Cell Transformation, Neoplastic / drug effects*
Cytoplasm / metabolism
Ferritins / genetics,  metabolism
Homeostasis
Humans
Iron / metabolism*
Iron-Regulatory Proteins / genetics,  metabolism
Osteosarcoma / drug therapy*,  metabolism
Oxidative Stress*
Phenylethyl Alcohol / analogs & derivatives,  pharmacology
Receptors, Transferrin / genetics,  metabolism
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
ES00260/ES/NIEHS NIH HHS; ES10344/ES/NIEHS NIH HHS; P30 ES000260/ES/NIEHS NIH HHS; P30 ES000260-40/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Antioxidants; 0/Arsenites; 0/Caffeic Acids; 0/Iron-Regulatory Proteins; 0/Receptors, Transferrin; 9007-73-2/Ferritins; E1UOL152H7/Iron; G960R9S5SK/caffeic acid phenethyl ester; ML9LGA7468/Phenylethyl Alcohol; N5509X556J/arsenite
Comments/Corrections

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