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26 March 2019 : Animal Research  

Arsenic Trioxide Inhibits the Metastasis of Small Cell Lung Cancer by Blocking Calcineurin-Nuclear Factor of Activated T Cells (NFAT) Signaling

Jin-Cheng Zheng1BCDE, Ke-Jie Chang1BCD, Yu-Xiang Jin2BCF, Xue-Wei Zhao2AD, Bing Li1ADFG*, Meng-Hang Yang1ABDEFG

DOI: 10.12659/MSM.913091

Med Sci Monit 2019; 25:2228-2237

Abstract

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 AND 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.

Keywords: Neoplasm Metastasis, Neovascularization, Pathologic, Small Cell Lung Carcinoma, Arsenic trioxide, Calcineurin, China, DNA-Binding Proteins, Endothelium, Vascular, Human Umbilical Vein Endothelial Cells, Intracellular Signaling Peptides and Proteins, Muscle Proteins, NFATC Transcription Factors, Receptors, CXCR, Up-Regulation, Vascular Endothelial Growth Factor A, rho GTP-Binding Proteins

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750