Zinc Chelation Mediates the Lysosomal Disruption without Intracellular ROS Generation.
We report the molecular mechanism for zinc depletion caused by TPEN (N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine) in neuroblastoma cells. The activation of p38 MAP kinase and subsequently caspase 3 is not due to or followed by redox imbalance or ROS generation, though these are commonly observed in literature. We found that TPEN is not responsible for ROS generation and the mechanism involves essentially lysosomal disruption caused by intracellular zinc depletion. We also observed a modest activation of Bax and no changes in the Bcl-2 proteins. As a result, we suggest that TPEN causes intracellular zinc depletion which can influence the breakdown of lysosomes and cell death without ROS generation.
Center for Natural Sciences and Humanities, Federal University of ABC, UFABC, Avenida dos Estados 5001, Bloco B, 09210-170 Santo André, SP, Brazil.
Andreza Cândido
AC
Matias
Center for Natural Sciences and Humanities, Federal University of ABC, UFABC, Avenida dos Estados 5001, Bloco B, 09210-170 Santo André, SP, Brazil.
Tânia Maria
TM
Manieri
Center for Natural Sciences and Humanities, Federal University of ABC, UFABC, Avenida dos Estados 5001, Bloco B, 09210-170 Santo André, SP, Brazil.
Giselle
G
Cerchiaro
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology*; D005029:Ethylenediamines / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D009336:Necrosis; D009447:Neuroblastoma / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002614:Chelating Agents; D005029:Ethylenediamines; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine