Increased uptake of zinc in malignant cells is associated with enhanced activation of MAPK signaling and P53-dependent cell injury.
Excess intracellular zinc has been demonstrated to be responsible for cell injury and cell death in various experimental as well as clinical models. While the cells possess a system of mechanisms regulating intracellular zinc homeostasis, their saturation by acutely increased zinc levels or by a sustained exposure to elevated zinc levels results in liberation of free zinc stores within the cells and ultimate cell damage and cell death. Here we report that in Hep-2 malignant cells enhanced uptake of zinc causes activation of mitogen-activated protein kinase (MAPK) signaling with resulting p53-dependent cell injury which can be significantly prevented by specific p53 inhibition and by prevention of oxidative stress. Our observations are consistent with the view that subacutely increased intracellular free zinc levels stimulate via oxidative stress p53-dependent pathways which are responsible for the final cell damage in tumor cells.
Rudolf
Emil
E
Department of Medical Biology and Genetics, Charles University, Prague, Faculty of Medicine, Hradec Králové, Czech Republic. rudolf@lfhk.cuni.cz
D017209:Apoptosis / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D018384:Oxidative Stress; D010766:Phosphorylation; D014407:Tumor Cells, Cultured / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000502:physiology*; D015032:Zinc / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015032:Zinc