1,3-Dicaffeoylquinic acid targeting 14-3-3 tau suppresses human breast cancer cell proliferation and metastasis through IL6/JAK2/PI3K pathway.
1,3-Dicaffeoylquinic acid targeting 14-3-3 tau suppresses human breast cancer cell proliferation and metastasis through IL6/JAK2/PI3K pathway.
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DOI：
10.1016/j.bcp.2019.113752
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发表时间：
2019-12
影响因子：
5.8
通讯作者：
Yuhang Zhou;Xiang Fu;Yanqing Guan;Mengting Gong;K. He;Bei Huang
中科院分区：
文献类型：
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作者：
Yuhang Zhou;Xiang Fu;Yanqing Guan;Mengting Gong;K. He;Bei Huang
14-3-3τ在乳腺癌的发生和转移中起重要作用，可作为新药靶蛋白。二咖啡酰奎宁酸(DCQA)是天然产物，具有抗氧化、抗菌、抗炎等活性。本研究探讨了DCQAs对乳腺癌细胞株MCF-7、MDA-MB-231的抗癌作用及其在三阴性乳腺癌中的作用机制。首先，我们筛选出能与14-3-3τ结合并对乳腺癌细胞有显著抑制作用的DCQAs。四甲基偶氮唑盐比色法、集落形成实验、跨膜迁移实验和流式细胞仪检测结果表明，1，3-DCQA是DCQA中14-3-3τ结合蛋白中抑制乳腺癌细胞增殖和转移的最佳结合蛋白，但对正常细胞是安全的。通过分子对接模拟、过表达和基因敲除实验，我们证实14-3-3-τ是1，3-DCQA的靶蛋白之一。真核细胞转录组测序和Western印迹分析表明，1，3-DCQA通过JAK/PI3K/AKT和Raf/ERK途径与14-3-3τ结合，抑制乳腺癌的增殖和转移，促进CREB(CREBBP、CREB5)上调的IL 6和CSF3的表达，并通过Bad/Bax/Caspase9信号通路诱导细胞凋亡。结果表明，1，3-DCQA可通过抑制14-3-3蛋白作为一种新的先导化合物用于乳腺癌的治疗。
14-3-3τ plays a critical role in tumorigenesis and metastasis of breast cancer and can be used as new drug target protein. Dicaffeoylquinic acids (DCQAs), natural products, have antioxidant, antimicrobial, and anti-inflammatory activities. In this study, the anticancer effects of DCQAs on breast cancer cells MCF-7, MDA-MB-231 cell lines and mechanism in triple negative breast cancer (TNBC) were investigated. First, we screened for DCQAs that could bind to 14-3-3τ and had a significant inhibitory effect on breast cancer cells. MTT, colony formation, transwell migration, and flow cytometric assays revealed that 1,3-DCQA was the best one of 14-3-3τ binding protein from DCQAs against breast cancer cell proliferation and metastasis but safe for normal cells. Through molecular docking simulation, overexpression and knockdown assays, we confirmed that 14-3-3τ was one of 1,3-DCQA target protein. Eukaryotic transcriptome sequencing and western blot analysis demonstrated that 1,3-DCQA binds to 14-3-3τ to prevent breast cancer proliferation and metastasis via Jak/PI3K/Akt and Raf/ERK pathway, which promote IL6 and CSF3 expression raised by CREB (CREBBP, CREB5) and induced cell apoptosis via Bad/Bax/caspase 9 signaling pathway. Our results provided evidence that 1,3-DCQA can be used as a novel lead compound against breast cancer by inhibition of 14-3-3 protein.