S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway

The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosis-inducing activity against various cells, especially tumor cells. Here, we present evidence that S100A8/A9 also has cell growth-promoting activity at low concentrations. Receptor of advanced glycation end product (RAGE) gene silencing and cotreatment with a RAGE-specific blocking antibody revealed that this activity was mediated via RAGE ligation. To inves- tigate the signaling pathways, MAPK phosphoryla- tion and NF-B activation were characterized in S100A8/A9-treated cells. S100A8/A9 caused a sig- nificant increase in p38 MAPK and p44/42 kinase phosphorylation, and the status of stress-activated protein kinase/JNK phosphorylation remained un- changed. Treatment of cells with S100A8/A9 also enhanced NF-B activation. RAGE small interfer- ing RNA pretreatment abrogated the S100A8/A9- induced NF-B activation. Our data indicate that S100A8/A9-promoted cell growth occurs through RAGE signaling and activation of NF-B. J. Leu- koc. Biol. 83: 1484-1492; 2008.