Arsenic Trioxide Inhibits the Metastasis of Small Cell Lung Cancer by Blocking Calcineurin-Nuclear Factor of Activated T Cells (NFAT) Signaling
Arsenic Trioxide Inhibits the Metastasis of Small Cell Lung Cancer by Blocking Calcineurin-Nuclear Factor of Activated T Cells (NFAT) Signaling
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DOI：
10.12659/msm.913091
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发表时间：
2019-03
期刊：
影响因子：
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通讯作者：
Jin-Cheng Zheng;Ke-Jie Chang;Yuxiang Jin;Xuewei Zhao;Bing Li;Meng-hang Yang
中科院分区：
文献类型：
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作者：
Jin-Cheng Zheng;Ke-Jie Chang;Yuxiang Jin;Xuewei Zhao;Bing Li;Meng-hang Yang
背景三氧化二砷（As 2 O3）对肺癌的抑制作用已有临床前研究报道。然而，其对小细胞肺癌（SCLC）的影响却很少探索。钙调神经磷酸酶及其底物活化T细胞核因子（NFAT）介导VEGF下游信号传导，在内皮细胞活化和肿瘤转移过程中起关键作用。本研究旨在探讨As 2 O3对小细胞肺癌内皮细胞活化和转移的抑制作用及其可能的机制。材料/方法体外培养人脐静脉内皮细胞（HUVECs）。采用Cell Counting Kit-8法和细胞迁移实验检测As 2 O3对HUVECs增殖和迁移的影响。通过定量PCR和蛋白质印迹法评估钙调神经磷酸酶、NFAT、唐氏综合征候选区域1（DSCR 1）下游因子和钙调神经磷酸酶内源性抑制剂的水平。裸鼠尾静脉注射NCI-H446细胞建立SCLC体内转移模型。用As 2 O3或钙调磷酸酶抑制剂治疗荷瘤小鼠10天，之后评估肿瘤在靶器官中的转移。结果As 2 O3可明显抑制内皮细胞的增殖和迁移。此外，As 2 O3抑制钙调神经磷酸酶，NFAT和下游靶基因CXCR 7和RND 1的表达水平，而它上调DSCR 1的水平。As_2O_3和钙调神经磷酸酶抑制剂对小细胞肺癌的转移均有明显的抑制作用，且无明显毒副作用。结论As 2 O3对SCLC的内皮细胞活化和转移有明显的抑制作用，其机制可能与上调DSCR 1，阻断Calcineurin-NFAT信号通路有关。
Background The inhibitory effect of arsenic trioxide (As2O3) on lung cancer has been reported in some preclinical studies. However, its effect on small cell lung cancer (SCLC) has been poorly explored. Calcineurin and its substrate, nuclear factor of activated T cells (NFAT), mediate the downstream signaling of VEGF, and is critical in the process endothelium activation and tumor metastasis. In this study, we aimed to evaluate whether As2O3 had inhibitory effects on endothelial cells activation and the metastasis of SCLC, and to explore the possible mechanisms. Material/Methods In vitro, human umbilical vein endothelial cells (HUVECs) were used. Cell Counting Kit-8 assay and cell migration assay were performed to determine the effect of As2O3 on HUVECs proliferation and migration. The level of calcineurin, NFAT, downstream factors for Down syndrome candidate region 1 (DSCR1), and the endogenous inhibitor of calcineurin, were evaluated by quantitative PCR and western blotting. In vivo, SCLC metastasis models were established by injecting NCI-H446 cells into tail veins of nude mice. Tumor-bearing mice were treated with As2O3 or calcineurin inhibitor for 10 days, after which tumor metastasis in target organs was evaluated. Results As2O3 significantly inhibited the proliferation and migration of endothelial cells. Also, As2O3 inhibited the expression levels of calcineurin, NFAT, and the downstream target genes CXCR7 and RND1, while it upregulated the level of DSCR1. Both As2O3 and calcineurin inhibitor exhibited notable inhibitory effect on the metastasis of SCLC, without obvious side effects. Conclusions These findings suggested that As2O3 had remarkable inhibitory effects on the endothelial cell activation and SCLC metastasis, and the mechanism might be related to the blocking of calcineurin-NFAT signaling by upregulating DSCR1.