Phytochemicals inhibit migration of triple negative breast cancer cells by targeting kinase signaling
Phytochemicals inhibit migration of triple negative breast cancer cells by targeting kinase signaling
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DOI：
10.1186/s12885-019-6479-2
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发表时间：
2020-01-02
期刊：
影响因子：
3.8
通讯作者：
Tavana, Hossein
中科院分区：
文献类型：
--
作者：
Thakuri, Pradip Shahi;Gupta, Megha;Tavana, Hossein
细胞迁移和侵袭是癌细胞转移传播的重要过程。在开发针对致癌信号的新疗法以消除癌细胞和缩小肿瘤方面取得了重大进展。然而，固有的异质性和治疗诱导的药物适应通常使癌细胞亚群能够在治疗中存活。除了局部复发，这些细胞逃离原发肿瘤，通过基质进入循环并转移到不同的器官，导致无法治愈的疾病。因此，阻断癌细胞迁移和侵袭的治疗方法可能抑制或减少转移，显著改善癌症治疗。这对于目前缺乏靶向药物的癌症，如三阴性乳腺癌，尤其重要。方法采用细胞迁移、3D侵袭、斑马鱼转移模型和43种蛋白激酶磷酸化分析9株三阴性乳腺癌（triple negative breast cancer， TNBC）细胞株，研究非西汀和槲皮素对TNBC细胞迁移、侵袭和转移的抑制作用。结果非西汀和槲皮素对9种TNBC细胞株的迁移均有较好的抑制作用，分别达到76%和74%。此外，治疗显著降低了高运动TNBC细胞从球体向胶原基质的三维侵袭及其在体内的转移。非瑟酮和槲皮素通常靶向致癌PI3K/AKT通路的不同成分和底物，并显著降低其活性。此外，这两种化合物都破坏了MAPK和STAT通路中几种蛋白激酶的活性。我们使用这些信号蛋白特异性的分子抑制剂来确定这两种植物化学物质对TNBC细胞的迁移抑制作用。结论：非瑟汀和槲皮素通过多种途径干扰癌蛋白激酶的活性，有效抑制转移性TNBC细胞的迁移。
Background Cell migration and invasion are essential processes for metastatic dissemination of cancer cells. Significant progress has been made in developing new therapies against oncogenic signaling to eliminate cancer cells and shrink tumors. However, inherent heterogeneity and treatment-induced adaptation to drugs commonly enable subsets of cancer cells to survive therapy. In addition to local recurrence, these cells escape a primary tumor and migrate through the stroma to access the circulation and metastasize to different organs, leading to an incurable disease. As such, therapeutics that block migration and invasion of cancer cells may inhibit or reduce metastasis and significantly improve cancer therapy. This is particularly more important for cancers, such as triple negative breast cancer, that currently lack targeted drugs. Methods We used cell migration, 3D invasion, zebrafish metastasis model, and phosphorylation analysis of 43 protein kinases in nine triple negative breast cancer (TNBC) cell lines to study effects of fisetin and quercetin on inhibition of TNBC cell migration, invasion, and metastasis. Results Fisetin and quercetin were highly effective against migration of all nine TNBC cell lines with up to 76 and 74% inhibitory effects, respectively. In addition, treatments significantly reduced 3D invasion of highly motile TNBC cells from spheroids into a collagen matrix and their metastasis in vivo. Fisetin and quercetin commonly targeted different components and substrates of the oncogenic PI3K/AKT pathway and significantly reduced their activities. Additionally, both compounds disrupted activities of several protein kinases in MAPK and STAT pathways. We used molecular inhibitors specific to these signaling proteins to establish the migration-inhibitory role of the two phytochemicals against TNBC cells. Conclusions We established that fisetin and quercetin potently inhibit migration of metastatic TNBC cells by interfering with activities of oncogenic protein kinases in multiple pathways.