Abstract 4125: The effects of S100B on cell signaling in malignant melanoma

Abstract

Abstract Establishing the mechanism by which S100B effects ERK and its downstream proteins will provide valuable insight into the role of S100B in the progression of melanoma and potentially aid in developing new pharmacological drugs. The protein S100B is an effective prognostic marker for human malignant melanoma. Increased levels of serum S100B are predictive of disease stage, increased recurrence, and low overall survival. It has previously been found that S100B directly interacts with the tumor suppressor protein p53, down-regulating its protein levels, thereby allowing damaged cells to proliferate and mutations to propagate. S100B has also been implicated in several other signaling pathways, including the MAPK pathway. The initial hypothesis tested was that S100B inhibits the phosphorylation of ERK targets in a calcium-dependent manner. The S100B binding motif has been found to overlap with the ERK binding motif, suggesting that S100B binds the targets and physically prevents ERK from interacting with and subsequently phosphorylating them. ERK kinase assays revealed that the addition of S100B in the presence of calcium decreased ERK phosphorylation of RSK, but more dramatically Elk-1. Additionally, RSK was detected in S100B pull-downs in the presence of calcium; however, it was not detected in the presence of the calcium chelator EDTA. Over-expression of normal human S100B, but not a mutant S100B incapable of binding calcium, results in decreased phosphorylated RSK at Thr573, yet increased phosphorylated ERK, interestingly. Since a rise in serum S100B levels is indicative of tumor progression, it was also of interest to see if the addition of extracellular S100B alone is sufficient to elicit the same signaling response. Preliminary data shows an increase in phosphorylated ERK after the addition of low concentrations of extracellular S100B, as well as effects on ERK targets. We demonstrate that the calcium-binding protein S100B affects the MAPK pathway by simultaneously increasing phosphorylated ERK and decreasing phosphorylated RSK and Elk-1, together which could have a significant impact on cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4125.