Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
Institute of Pharmacology, Heidelberg University, Germany.
Mol Oncol. 2020 Jun;14(6):1134-1151. doi: 10.1002/1878-0261.12678. Epub 2020 Apr 28.
Changes in intracellular calcium (Ca ) signaling can modulate cellular machinery required for cancer progression. Neuronal calcium sensor 1 (NCS1) is a ubiquitously expressed Ca -binding protein that promotes tumor aggressiveness by enhancing cell survival and metastasis. However, the underlying mechanism by which NCS1 contributes to increased tumor aggressiveness has yet to be identified. In this study, we aimed to determine (a) whether NCS1 expression changes in response to external stimuli, (b) the importance of NCS1 for cell survival and migration, and (c) the cellular mechanism(s) through which NSC1 modulates these outcomes. We found that NCS1 abundance increases under conditions of stress, most prominently after stimulation with the pro-inflammatory cytokine tumor necrosis factor α, in a manner dependent on nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). We found that NFκB signaling is activated in human breast cancer tissue, which was accompanied by an increase in NCS1 mRNA expression. Further exploration into the relevance of NCS1 in breast cancer progression showed that knockout of NCS1 (NCS1 KO) caused decreased cell survival and motility, increased baseline intracellular Ca levels, and decreased inositol 1,4,5-trisphosphate-mediated Ca responses. Protein kinase B (Akt) activity was decreased in NCS1 KO cells, which could be rescued by buffering intracellular Ca . Conversely, Akt activity was increased in cells overexpressing NCS1 (NCS1 OE). We therefore conclude that NCS1 acts as cellular stress response protein up-regulated by stress-induced NFκB signaling and that NCS1 influences cell survival and motility through effects on Ca signaling and Akt pathway activation.
细胞内钙（Ca ）信号的变化可以调节癌症进展所需的细胞机制。神经元钙传感器 1（NCS1）是一种广泛表达的 Ca 结合蛋白，通过增强细胞存活和转移来促进肿瘤侵袭性。然而，NCS1 促进肿瘤侵袭性的潜在机制尚未确定。在这项研究中，我们旨在确定：（a）NCS1 表达是否对外界刺激发生变化；（b）NCS1 对细胞存活和迁移的重要性；（c）NCS1 调节这些结果的细胞机制。我们发现，在应激条件下，NCS1 丰度增加，在受到促炎细胞因子肿瘤坏死因子 α刺激时最为明显，这一过程依赖于核因子 kappa-轻链增强子的 B 细胞（NFκB）。我们发现 NFκB 信号在人乳腺癌组织中被激活，伴随着 NCS1 mRNA 表达的增加。进一步探索 NCS1 在乳腺癌进展中的相关性表明，NCS1 敲除（NCS1 KO）导致细胞存活和迁移减少，基础细胞内 Ca 水平升高，肌醇 1,4,5-三磷酸介导的 Ca 反应减少。蛋白激酶 B（Akt）活性在 NCS1 KO 细胞中降低，通过缓冲细胞内 Ca 可以得到挽救。相反，在过表达 NCS1 的细胞（NCS1 OE）中 Akt 活性增加。因此，我们得出结论，NCS1 作为细胞应激反应蛋白，由应激诱导的 NFκB 信号上调，通过对 Ca 信号和 Akt 通路激活的影响来影响细胞存活和迁移。
