1,3-Dicaffeoylquinic acid targeting 14-3-3 tau suppresses human breast cancer cell proliferation and metastasis through IL6/JAK2/PI3K pathway

摘要

14-3-3 tau 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 14-3-3 tau 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 14-3-3 tau 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 14-3-3 tau was one of 1,3-DCQA target protein. Eukaryotic transcriptome sequencing and western blot analysis demonstrated that 1,3-DCQA binds to 14-3-3 tau 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.