The Effects of Extracellular Zinc Depletion on Zinc Homeostasis and Oxidative Stress Responses in Cancer Cell Lines

Abstract

Zinc (Zn) deficiency is thought to be involved in the development of cancer by increasing oxidative stress-mediated DNA damage. However, the relationship between tumor development and Zn status is complex since Zn concentrations differ between various cancers. Little is known about the effects of Zn depletion after cancer initiation. Hence we examined the effects of DTPA (diethylenetriaminepenta-acetic acid) induced Zn depletion on homeostasis and oxidative stress responses in rat hepatoma (H4IIE) and thymic lymphoma (C58NT) cell lines. DTPA (50 uM) added to the media reduced Zn efflux from H4IIE cells but increased efflux from C58NT cells. RT-PCR analyses revealed that DTPA did not affect ZnT-1 or ZnT-2 mRNA levels in either cell line but reduced metallothionein mRNA only in H4IIE cells. DTPA treatment increased reactive oxygen species generation in both cells lines, but reduced cell viability only in C58NT cells. DTPA reduced synthesis and concentrations of glutathione in C58NT cells but no changes were observed in H4IIE cells. These data indicate that H4IIE cells are better able to respond to DTPA-induced zinc deprivation, conserving intracellular zinc and maintaining glutathione levels and cell viability.