Zinc-mediated regulation of caspases activity: dose-dependent inhibition or activation of caspase-3 in the human Burkitt lymphoma B cells (Ramos)

Abstract

Divalent cations, including Zinc and Manganese ions, are important modulators of cell activation. We investigated the ability of these two divalent cations to modulate apoptosis in human Burkitt lymphoma B cells line (Ramos). We found that Zinc (from 10 to 50 mM) inhibited Manganese-induced caspase-3 activation and apoptosis of Ramos cells. Higher concentration of Zinc (50 to 100 mM) did not prevent Manganese-mediated apoptosis but rather increased cell death among Ramos cells. This Zinc-mediated cell death was associated with apoptotic features such as cell shrinkage, the presence of phosphatidylserine residues on the outer leaflet of the cells, chromatin condensation, DNA fragmentation and decrease of mitochondrial transmembrane potential. Zincmediated apoptosis was associated with caspase-9 and caspase-3 activation as revealed by the appearance of active p35 fragment of caspase-9 and p19 and p17 of caspase-3 as well as in vivo cleavage of PARP and of a cell-permeable fluorogenic caspase-3 substrate (Phiphilux-G 1 D 2 ). Both Zincmediated apoptosis and caspase-3 activation were prevented by the cell-permeable, broad-spectrum inhibitor of caspases (zVAD-fmk) or overexpression of bcl-2. In addition, we show that Zinc-induced loss of transmembrane mitochondrial potential is a caspase-independent event, since it is not modified by the presence of zVAD-fmk, which is inhibited by overexpression of bcl-2. These results indicate that depending on its concentration, Zinc can exert opposite effects on caspase-3 activation and apoptosis in human B lymphoma cells: concentrations below 50 mM inhibit caspase-3 activation and apoptosis whereas higher concentrations of Zinc activate a death pathway associated with apoptotic-like features and caspase-3 activation. Cell Death and Differentiation (2001) 8, 152 ± 161.

Anticancer Activity of the Antibiotic Clioquinol

“…Iron and copper are redox-active metals, which may be more redox active when complexed with some chelators, and are well recognized to be cytotoxic. Zinc, on the other hand, is not a redox-active metal (26) and has been reported to inhibit apoptosis under certain circumstances (27,28). We therefore focused on the effects of treating cells with clioquinol and zinc.…”

Activation of Caspase-3 in HL-60 Cells Treated with Pyrithione and Zinc

“…On the contrary, Zn at concentrations of 10 to 50 mM attenuated manganese-induced apoptosis, but higher concentrations of Zn (50-100 mM) increased cell death in human Burkitt lymphoma B cells. 5) Zn had no effect on interleukin-3-mediated apoptosis in murine B lymphoid cells but enhanced CD95-mediated apoptosis in human T lymphoid cells. 6) Thus, Zn has opposite effects on the induction of apoptosis, but the mechanism by which Zn affects apoptosis remains unclear.…”

Zinc-mediated Allosteric Inhibition of Caspase-6

“…Mouse embryos on a zinc-deficient diet suffer from neural tube defects, retarded development, and apoptotic cell death (26), likely due to loss of zinc-mediated caspase inhibition. The inhibition of caspases by transition metals, including zinc and copper, was reported soon after the discovery of caspases (27)(28)(29). Exposure of caspases to metal ions alters their cell death potential.…”