Metal ions such as Ca
2+, Mg
2+, or Zn
2+, are important for many cell functions, for example, signal transduction and the modulation of enzyme activity. The relationship between apoptosis and metal cations, especially Ca
2+, has been described in many reports. We have investigated the role of metal cations in the regulation of apoptosis in the mouse neuroblastoma cell line, Neuro-2A. When Neuro-2A cells were treated with ethylene diaminetetraacetic acid (EDTA), apoptosis was detected as growth inhibition, DNA fragmentation with a ladder pattern in agarose gel electrophoresis, and nuclear decomposition. However, in case of the treatment with ethylene glycol bis- (β-aminoethyl ether) N, N, N', N'-tetraacetic acid (EGTA), which has a higher chelating specificity for Ca
2+ than EDTA, DNA fragmentation was not detected. Moreover, the apoptosis induced by EDTA was inhibited by exogenous Zn
2+. The membrane permeable Zn
2+ chelator N, N, N', N'-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN) also induced apoptosis of the Neuro-2A cells, and addition of equimolar exogenous Zn
2+ or Cu
2+, but not Mn
2+ or Fe
2+, prevented TPEN-induced apoptosis. The results suggest that Zn
2+ may be a key regulator of apoptosis in Neuro-2A cells.
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