Regulation of S100A8/A9 (calprotectin) binding to tumor cells by zinc ion and its implication for apoptosis-inducing activity.
S100A8/A9 (calprotectin), which is released by neutrophils under inflammatory conditions, has the capacity to induce apoptosis in various cells. We previously reported that S100A8/A9 induces apoptosis of EL-4 lymphoma cells via the uptake of extracellular zinc in a manner similar to DTPA, a membrane-impermeable zinc chelator. In this study, S100A8/A9-induced apoptosis was examined in several cell lines that are weakly sensitive to DTPA, suggesting S100A8/A9 is directly responsible for apoptosis in these cells. Since zinc inhibits apoptosis of MM46, one of these cells, the regulation by zinc of the capacity of S100A8/A9 to bind MM46 cells was studied. When MM46 cells were incubated with S100A8/A9 in standard or zinc-depleted medium, the amounts of S100A8/A9 bound to cells was markedly lower at 3 h than at 1 h. In contrast, when MM46 cells were incubated with S100A8/A9 in the presence of high levels of zinc, binding to cells was the same at 1 and 3 h. When the cells were permeabilized with saponin prior to analysis, a larger amount of cell-associated S100A8/A9 was detected at 3 h. The amount was further increased in cells treated with chloroquine, suggesting that S100A8/A9 was internalized and degraded in lysosomes. Although it has been reported that S100A8/A9 binds to heparan sulfate on cell membranes, the amount of S100A8/A9 bound to MM46 cells was not reduced by heparinase treatment, but was reduced by trypsin treatment. These results suggest that S100A8/A9 induces apoptosis by direct binding to MM46 cells, and that this activity is regulated by zinc.
Nakatani
Yuichi
Y
Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan.
Yamazaki
Masatoshi
M
Chazin
Walter J
WJ
Yui
Satoru
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002614:Chelating Agents / Q000633:toxicity; D006497:Heparan Sulfate / Q000494:pharmacology; D006801:Humans; D007478:Iontophoresis; D039841:Leukocyte L1 Antigen Complex / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D051379:Mice; D004369:Pentetic Acid / Q000633:toxicity; D011485:Protein Binding / Q000187:drug effects; D015032:Zinc / Q000494:pharmacology*
D002614:Chelating Agents; D006497:Heparan Sulfate; D039841:Leukocyte L1 Antigen Complex; D004369:Pentetic Acid; D015032:Zinc