title: Iron chelators reduce chromosomal breaks in ataxia-telangiectasia cells.
abstract: Ataxia-telangiectasia (A-T) is characterized by ataxia, genomic instability, and increased cancer incidence. Previously, iron chelator concentrations which suppressed normal cell colony formation increased A-T cell colony formation. Similarly, iron chelators preferentially increased A-T cell colony formation following peroxide exposure compared to normal cells. Last, A-T cells exhibited increased short-term sensitivity to labile iron exposure compared to normal cells, an event corrected by recombinant ATM (rATM) expression. Since chromosomal damage is important in A-T pathology and iron chelators exert beneficial effects on A-T cells, we hypothesized that iron chelators would reduce A-T cell chromosomal breaks. We treated A-T, normal, and A-T cells expressing rATM with labile iron, iron chelators, antioxidants, and t-butyl hydroperoxide, and examined chromosomal breaks and ATM activation. Additionally, the effect of ATM-deficiency on transferrin receptor (TfR) expression and TfR activity blockage in A-T and syngeneic A-T cells expressing rATM was examined. We report that (1) iron chelators and iron-free media reduce spontaneous and t-butyl hydroperoxide-induced chromosomal breaks in A-T, but not normal, or A-T cells expressing rATM; (2) labile iron exposure induces A-T cell chromosomal breaks, an event lessened with rATM expression; (3) desferal, labile iron, and copper activate ATM; (4) A-T cell TfR expression is lowered with rATM expression and (5) blocking TfR activity with anti-TfR antibodies increases A-T cell colony formation, while lowering chromosomal breaks. ATM therefore functions in iron responses and the maintenance of genomic stability following labile iron exposure.
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center in Shreveport, 1501 Kings Hwy Shreveport, LA 71130, United States.
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Shackelford
authors.forename: Yumei
authors.initials: Y
authors.lastname: Fu
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Manuszak
authors.forename: Torrie C
authors.initials: TC
authors.lastname: Brooks
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Sequeira
authors.forename: Suming
authors.initials: S
authors.lastname: Wang
authors.forename: Mary
authors.initials: M
authors.lastname: Lowery-Nordberg
authors.forename: Anping
authors.initials: A
authors.lastname: Chen
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D018929:Cell Culture Techniques; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D019457:Chromosome Breakage / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics; D003676:Deferoxamine / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007501:Iron / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology*; D009153:Mutagens / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011990:Receptors, Transferrin / Q000037:antagonists & inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D012459:Salicylates / Q000494:pharmacology; D008063:Thioctic Acid / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D000906:Antibodies; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C433928:EUK-134; D007502:Iron Chelating Agents; D009153:Mutagens; D009942:Organometallic Compounds; D011990:Receptors, Transferrin; D011993:Recombinant Fusion Proteins; D012459:Salicylates; D025521:Tumor Suppressor Proteins; D008063:Thioctic Acid; D002392:Catechin; D020122:tert-Butylhydroperoxide; C045651:epigallocatechin gallate; D007501:Iron; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D003676:Deferoxamine