Abstract
S100A14 is an EF-hand containing calcium-binding protein of the S100 protein family that exerts its biological effects on different types of cells. However, exact extracellular roles of S100A14 have not been clarified yet. Here we investigated the effects of S100A14 on esophageal squamous cell carcinoma (ESCC) cell lines. Results demonstrated that low doses of extracellular S100A14 stimulate cell proliferation and promote survival in KYSE180 cells through activating ERK1/2 MAPK and NF-κB signaling pathways. Immunoprecipitation assay showed that S100A14 binds to receptor for advanced glycation end products (RAGE) in KYSE180 cells. Inhibition of RAGE signaling by different approaches including siRNA for RAGE, overexpression of a dominant-negative RAGE construct or a RAGE antagonist peptide (AmphP) significantly blocked S100A14-induced effects, suggesting that S100A14 acts via RAGE ligation. Furthermore, mutation of the N-EF hand of S100A14 (E39A, E45A) virtually reduced 10 µg/ml S100A14-induced cell proliferation and ERK1/2 activation. However, high dose (80 µg/ml) of S100A14 causes apoptosis via the mitochondrial pathway with activation of caspase-3, caspase-9, and poly(ADP-ribose) polymerase. High dose S100A14 induces cell apoptosis is partially in a RAGE-dependent manner. This is the first study to demonstrate that S100A14 binds to RAGE and stimulates RAGE-dependent signaling cascades, promoting cell proliferation or triggering cell apoptosis at different doses.
Highlights
S100 proteins are small calcium-binding proteins of the EF hand motif which can function as both intra- and extracellular signaling molecules
We found that low doses of exogenous S100A14 activate ERK1/2 and NF-kB signaling, stimulating cell proliferation or promoting cell survival via receptor for advanced glycation end products (RAGE) ligation; while high dose of S100A14 triggers apoptosis and increases the production of ROS in a RAGE-dependent manner
30 min incubation of mS100A14-N protein abrogated ERK1/2 activation (Figure 4H), indicating that key amino acid of N-EF hand might play an important role on S100A14 function. These results suggest that the interaction between RAGE and S100A14 may play an important role in cell proliferation and survival by activating ERK1/2 and NF-kB signaling
Summary
S100 proteins are small calcium-binding proteins of the EF hand motif which can function as both intra- and extracellular signaling molecules. They exert a broad range of intracellular functions through the modulation of their subcellular localization and interacting with specific target proteins, responsible for cell growth, differentiation, motility, and cell cycle regulation [1,2]. RAGE binds to multiple families of ligands, such as advanced glycation end products (AGEs), S100s, and amphoterin, and plays a key role in diabetes, inflammation, and cancer [5,10]. RAGE ligation is known to activate multiple signaling pathways such as MAPK, JNKs, Cdc42/Rac, together with activation of transcription factors AP-1, NF-kB, etc
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