State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
PLoS One. 2011 Apr 29;6(4):e19375. doi: 10.1371/journal.pone.0019375.
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.
S100A14 是 S100 蛋白家族中的一种 EF 手钙结合蛋白，对不同类型的细胞发挥其生物学效应。然而，S100A14 的确切细胞外作用尚未阐明。在这里，我们研究了 S100A14 对食管鳞状细胞癌（ESCC）细胞系的影响。结果表明，低剂量的细胞外 S100A14 通过激活 ERK1/2 MAPK 和 NF-κB 信号通路刺激 KYSE180 细胞增殖并促进其存活。免疫沉淀试验表明，S100A14 在 KYSE180 细胞中与晚期糖基化终产物受体（RAGE）结合。通过不同方法抑制 RAGE 信号通路，包括 RAGE 的 siRNA、过表达显性负性 RAGE 构建体或 RAGE 拮抗剂肽（AmphP），显著阻断了 S100A14 诱导的作用，表明 S100A14 通过 RAGE 连接发挥作用。此外，S100A14 的 N-EF 手突变（E39A、E45A）实际上降低了 10 µg/ml S100A14 诱导的细胞增殖和 ERK1/2 激活。然而，高剂量（80 µg/ml）的 S100A14 通过激活 caspase-3、caspase-9 和聚（ADP-核糖）聚合酶引起线粒体途径的细胞凋亡。高剂量的 S100A14 诱导细胞凋亡在一定程度上依赖于 RAGE。这是第一项表明 S100A14 与 RAGE 结合并刺激 RAGE 依赖性信号级联反应的研究，在不同剂量下促进细胞增殖或触发细胞凋亡。
