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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 16 - 2025 |
doi: 10.3389/fphar.2025.1496511
Anti-TNBC effects of Lappaol F by targeting epithelial-mesenchymal transition via regulation of GSK-3β/YAP/β-catenin and PI3K/AKT pathways
Provisionally accepted- 1 Guangzhou University of Chinese Medicine, Guangzhou, China
- 2 Hainan Medical University, Haikou, Hainan Province, China
Purpose: Lappaol F (LAF), a lignan extracted from Fructus Arctii (F. arctii), has a wide spectrum of anti-tumor effects, including inhibition of TNBC cell growth. However, the pharmacological mechanism of LAF targeting epithelialmesenchymal transition (EMT) to inhibit TNBC growth remains poorly understood. The present study aimed to reveal the potential mechanism of LAF against TNBC by in vivo and in vitro experiments. Methods: In situ, transplantation-induced MDA-MB-231 solid tumor model in NCG mice and cultured MDA-MB-231 and Hs-578T cells were used to evaluate the anti-TNBC effect of LAF. Flow cytometry, wound healing, transwell assay, Western blot, RT-PCR, and immunofluorescence analysis were carried out to investigate the pharmacological mechanism of LAF against TNBC. Results: LAF significantly inhibited the growth of MDA-MB-231 tumors, with down-regulated tumor level of vimentin and up-regulated level of ZO-1. In MDA-MB-231 and Hs-578T cells, LAF markedly suppressed cell proliferation, migration and invasion, and promoted apoptosis. Similarly, LAF increased the expression of ZO-1 and occludin proteins in MDA-MB-231 cells, and inhibited the expression of vimentin and Snail&Slug proteins in MDA-MB-231 and Hs-578T cells, as well as the expression of N-caderin in Hs-578T cells. Moreover, LAF also inhibited the phosphorylation of GSK-3β, thereby inhibited the downstream nuclear translocation of β-catenin and the expression of YAP.Furthermore, LAF significantly inhibited the expression of PI3K and AKT, and the phosphorylation of downstream mTOR.Conclusions: LAF showed anti-TNBC effect both in vitro and in vivo.Reversal of EMT by inhibiting GSK-3β/YAP/β-catenin signaling and PI3K/AKT/mTOR signaling contributes to the effect.
Keywords: Arctium lappa L, lappaol F, Triple negative breast cancer, Epithelial-Mesenchymal Transition, GSK-3β/YAP/β-catenin signaling, PI3K/AKT signaling AIG, Anchorage-independent growth, AKT, receptor serine/threonine kinases, AR, Anoikis resistance
Received: 14 Sep 2024; Accepted: 17 Jan 2025.
Copyright: © 2025 Qiqi, Zhiping, Xiaofeng, Zhuohui, Yingjie and Xiao-Ling. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Shen Xiao-Ling, Guangzhou University of Chinese Medicine, Guangzhou, China
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