Iron chelators increase the resistance of Ataxia telangeictasia cells to oxidative stress.
Ataxia telangeictasia (A-T) is an autosomal recessive disorder characterized by immune dysfunction, genomic instability, chronic oxidative damage, and increased cancer incidence. Previously, desferal was found to increase the resistance of A-T, but not normal cells to exogenous oxidative stress in the colony forming-efficiency assay, suggesting that iron metabolism is dysregulated in A-T. Since desferal both chelates iron and modulates gene expression, we tested the effects of apoferritin and the iron chelating flavonoid quercetin on A-T cell colony-forming ability. We demonstrate that apoferritin and quercetin increase the ability of A-T cells to form colonies. We also show that labile iron levels are significantly elevated in Atm-deficient mouse sera compared to syngeniec wild type mice. Our findings support a role for labile iron acting as a Fenton catalyst in A-T, contributing to the chronic oxidative stress seen in this disease. Our findings further suggest that iron chelators might promote the survival of A-T cells and hence, individuals with A-T.
Shackelford
Rodney E
RE
Iowa Cancer Research Foundation, 11043 Aurora Avenue, Urbandale, IA 50322, USA.
Manuszak
Ryan P
RP
Johnson
Cybele D
CD
Hellrung
Daniel J
DJ
Link
Charles J
CJ
Wang
Suming
S
D000818:Animals; D001052:Apoferritins / Q000494:pharmacology*; D001260:Ataxia Telangiectasia / Q000188:drug therapy* / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004351:Drug Resistance; D005347:Fibroblasts / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D011794:Quercetin / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007502:Iron Chelating Agents; D025521:Tumor Suppressor Proteins; D001052:Apoferritins; D011794:Quercetin; D007501:Iron; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases