Regulation of S100A8/A9 (Calprotectin) Binding to Tumor Cells byZinc Ion and Its Implication for Apoptosis‐Inducing Activity

Abstract

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.

Alcohol Treatment of Oral Streptococcus Spp. Increased the Entry of Human Papillomavirus Type 16 into Non-Malignant and Oral Squamous Cell Carcinoma Cells

“…attachment, metabolism of ETOH and a requirement for HOK synthesis of HSBPs, such as syndecan. In the next assay we explored specificity for syndecan-1 which is also linked to selective cell membrane protein exemplified by calprotectin (S100) [49,[54][55][56].…”

“…Significance to this finding is suggested by these facts for syndecan expression. Syndecan-1,4 activities require NADPH oxidase enzyme activity and heavy metal (zinc) deposition through S100A8/A9 complex formation which may influence metalloproteinase degradation of extracellular proteins, an important function for transformed cell migration [56]. S100A8/A9 is also reported to be a mediator in growth regulation of keratinocytes and epithelial inducible inflammatory activity which can be initiated through Toll-like receptors that recognize Streptococci spp [56].…”

“…Syndecan-1,4 activities require NADPH oxidase enzyme activity and heavy metal (zinc) deposition through S100A8/A9 complex formation which may influence metalloproteinase degradation of extracellular proteins, an important function for transformed cell migration [56]. S100A8/A9 is also reported to be a mediator in growth regulation of keratinocytes and epithelial inducible inflammatory activity which can be initiated through Toll-like receptors that recognize Streptococci spp [56]. Another S100; A10 sub unit is found with Annexin A2 and as noted S. salivarius (109-2, AA: 11.6 mM) (5X10 3 cfu/mL) treatment with ETOH (50 mg/mL/10 mM) and washed then incubated with HOK/HPV 16B cells (3h), which were pre-treated with heparanase (100 ng/mL).…”

“…Annexin A2 expression leads to activation of EGFR and HPV 16 entry [57]. AA is also noted to induce apoptosis and proteoglycan/syndecancalprotectin interaction [56]. Stated above syndecan 1,4 expressions are recognized as factors for enhanced migratory activity of transformed and malignant HOK.…”

“…Syndecan also binds to collagens (I, III, and V), fibronectin, tenascin and other extracellular matrix non-collagenous proteins that facilitate migration [58]. Moreover, syndecan-1 can degrade HSBPs in a heparanase like manner to increase proliferation and metastatic potential of keratinocytes [50,51,56]. Lastly, syndecan-4 stimulates tumor cell proliferation with a decrease in binding of fibronectin by epithelial cells to accelerate ISSN: 2377-987X migration [58][59][60].…”