Increased Uptake of Zinc in Malignant Cells is Associated with Enhanced Activation of MAPK Signalling and P53-Dependent Cell Injury

Abstract

Summary: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.

Transient fluctuations of intracellular zinc ions in cell proliferation

“…At higher extracellular Zn 2+ concentrations (50 μM and 100 μM ZnSO 4 ) in a serum-free medium without significant metal-buffering capacity, the intracellular zincbuffering capacity of PC12 cells at physiological Zn 2+ concentrations is overwhelmed, and higher Zn 2+ concentrations occur. Excess intracellular Zn 2+ is responsible for cell injury and cell death through ERK-and p53-dependent apoptotic pathways [27,28].…”