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.

中文翻译：

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植物化学物质通过靶向激酶信号传导抑制三阴性乳腺癌细胞的迁移。


背景技术细胞迁移和侵袭是癌细胞转移扩散的重要过程。在开发针对致癌信号传导以消除癌细胞和缩小肿瘤的新疗法方面已取得重大进展。然而，固有的异质性和治疗引起的对药物的适应通常使癌细胞亚群能够在治疗中存活下来。除了局部复发之外，这些细胞逃离原发肿瘤并通过基质迁移进入循环并转移到不同的器官，导致无法治愈的疾病。因此，阻止癌细胞迁移和侵袭的疗法可以抑制或减少转移并显着改善癌症治疗。这对于目前缺乏靶向药物的癌症，例如三阴性乳腺癌，尤其重要。方法我们采用细胞迁移、3D侵袭、斑马鱼转移模型以及9个三阴性乳腺癌（TNBC）细胞系中43种蛋白激酶的磷酸化分析来研究非瑟酮和槲皮素对TNBC细胞迁移、侵袭和转移的抑制作用。结果 漆黄素和槲皮素对所有九种 TNBC 细胞系的迁移非常有效，抑制效果分别高达 76% 和 74%。此外，治疗显着减少了高活动性 TNBC 细胞从球体到胶原基质的 3D 侵袭及其体内转移。非瑟酮和槲皮素通常针对致癌 PI3K/AKT 途径的不同成分和底物，并显着降低其活性。此外，这两种化合物都会破坏 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 我们确定非瑟酮和槲皮素通过干扰多种途径中致癌蛋白激酶的活性，有效抑制转移性 TNBC 细胞的迁移。