Ginsenoside 20(S)-protopanaxadiol inhibits triple-negative breast cancer metastasis in vivo by targeting EGFR-mediated MAPK pathway. (April 2019)

• Record Type: Journal Article
• Authors: Peng, Bo; He, Rong; Xu, Qihua; Yang, Yifei; Hu, Qin; Hou, Hongping; Liu, Xinmin; Li, Jianrong
• Is Part Of: Pharmacological research. Volume 142(2019)
• Page Start: 1
• Page End: 13
• Publication Date: 2019-04
• Subjects: PPD 20S-protopanaxadiol -- TNBC triple-negative breast cancer -- ER estrogen receptor -- PR progesterone receptor -- HER2 human epidermal receptor 2 -- EGFR epidermal growth factor receptor -- EMT epithelial-mesenchymal transition -- MMP matrix metalloproteinase -- TIMP tissue of inhibitors of metalloproteinase -- ECM extracellular matrix -- MAPK mitogen-activated protein kinase -- ERK1/2 extracellular signal-regulated kinase1/2 -- JNK c-Jun N-terminal kinase -- BLI bioluminescence imaging -- EGF epidermal growth factor -- PMA phorbol-12-myristate-13-acetate; 20(S)-protopanaxadiol -- Metastasis -- Breast cancer -- EMT -- EGFR/MAPK pathways; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.02.003
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Metastasis is the primary cause of cancer recurrence and cancer related mortality in triple-negative breast cancer (TNBC). EGFR overexpression is in 50–75% TNBC and EGFR-mediated signaling has potential as an attractive therapeutic target in some specific subtypes of breast cancer due to its significant association with tumor metastasis and poor prognosis. Therefore, identification of promising therapeutic strategies targeting EGFR with higher specificity toward cancer metastasis is urgently needed. 20(S)-protopanaxadiol (PPD), one of the major active metabolites from Panax ginseng, has been widely reported to possess pleiotropic anticancer activities in various cancers. In this study, we investigated the effect of PPD against cancer metastasis and the related molecular mechanisms in TNBC in vitro and in vivo . PPD (>30 μM) suppressed cell proliferation by arresting cell cycle in G0/1 phase and triggering cells apoptosis as shown by cell viability assay, flow cytometry analysis and colony formation assay, whereas lower dose of PPD (<20 μM) decreased metastatic potential of MDA-MB-231 and SUM159 cells through direct inhibition of cell adhesion, motility and invasiveness. In TNBC xenograft and syngeneic models, PPD treatment markedly decreased tumor growth and lung metastasis. PPD reversed epithelial-mesenchymal transition (EMT), decreased the expression and activity of matrix metalloproteinases (MMPs) while increased the expression of tissue inhibitors of metalloproteinases (TIMPs) as shown by Western blot and gelatin zymography. Cell signaling pathways that control the expression or activation of these processes were investigated by Western blot and ELISA assay. PPD treatment reduced the phosphorylation of EGFR and down-regulated the activation ERK1/2, p38 and JNK signaling, which was further validated by using the agonists or inhibitors of EGFR and MAP kinases family. Collectively, these findings suggest that PPD holds therapeutic potential against the tumor metastasis of TNBC via targeting EGFR-mediated MAPK pathway.