Abstract
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.
Highlights
Zinc is one of the most abundant inorganic elements in mammalian cells, where it regulates a wide variety of biological activities including maintenance of structural as well as functional integrity of cells [2]
Despite the fact that inside cells zinc is mostly found in a bound form, its intracellular homeostasis has to be strictly regulated, as it has been amply demonstrated that increased intracellular zinc abundance contributes to cellular injury and, in some cases, leads to ultimate cell death [5]
Zinc induces the expression and phosphorylation of p53 Since zinc has been shown to produce oxidative stress and possibly damage DNA, we examined the level of p53 in treated Hep-2 cells
Summary
Zinc is one of the most abundant inorganic elements in mammalian cells, where it regulates a wide variety of biological activities including maintenance of structural as well as functional integrity of cells [2]. Despite the fact that inside cells zinc is mostly found in a bound form, its intracellular homeostasis has to be strictly regulated, as it has been amply demonstrated that increased intracellular zinc abundance contributes to cellular injury and, in some cases, leads to ultimate cell death [5]. Zinc transport and trafficking is generally regulated by two gene families – the ZnT proteins and the Zip family. ZnT and Zip proteins seem to have opposite roles in cellular zinc homeostasis, with ZnT transporters reducing intracellular cytoplasmic zinc levels by promoting zinc efflux from cells, while Zip transporters increase intracellular cytoplasmic zinc by promoting extracellular zinc translocation into cytoplasm [9]. Upon zinc starvation or excess exposure, particular zinc transporters show varying response rates in terms of their downregulation, upregulation and localization [9]
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