Inhibition of TPA‑induced metastatic potential by morin hydrate in MCF‑7 human breast cancer cells via the Akt/GSK‑3β/c‑Fos signaling pathway

Abstract

Plant flavonoid 2' ,3,4' ,5,7-pentahydroxyflavone (morin hydrate), isolated from the family Moraceae (Morus alba L.), is known to have anti-inflammatory and anticancer effects. However, its pharmaceutical effects on metastasis have not been fully elucidated to date. Therefore, the current study investigated the effects of morin hydrate on cancer metastasis in MCF-7 human breast cancer cells. The results showed that morin hydrate suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-indu ced cell migration and invasion via the inhibition of matrix metalloproteinase (MMP)-9 activity. Furthermore, gene expression level of MMP-9, MMP-7, urokinase plasminogen activator (uPA), uPA receptor (uPAR) and fibronectin were significantly decreased by morin hydrate treatment. Morin hydrate inhibited the phosphorylation of Akt and glycogen synthase kinase (GSK)-3β, and downregulated the expression of an activator protein-1 subunit c-Fos. In addition, the GSK-3β phosphorylation and c-Fos expression were suppressed by PI3K/Akt pathway inhibitors, LY294002 and wortmannin. Taken together, these results demonstrated that morin hydrate reduced the metastatic potential in TPA-treated MCF-7 human breast cancer cells via the inhibition of MMPs, uPA and uPAR, and the underlying Akt/GSK-3β/c-Fos pathway. Therefore, the present investigation suggested that morin hydrate may be a natural substance with a preventive potential for metastasis in breast cancer cells.

Flavonoids in Cancer Metastasis

“…Morin Hydrate . Morin hydrate, a flavonoid isolated from Morus alba L., inhibited metastatic potential of 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated MCF-7 breast cancer cells via the inhibition of MMPs, uPA, uPAR, and the Akt/GSK-3β/c-Fos pathway [ 87 ].…”

Systems pharmacology in combination with proteomics reveals underlying mechanisms of Xihuang pill against triple-negative breast cancer

“…As a natural pentahydroxyflavone, morin is an anti-tumor agent and well studied to exert an antimetastatic activity in TBNC via inhibiting breast cancer cell adhesion to endothelial cells and epithelial-mesenchymal transition (EMT) [51] or suppressing highly metastatic breast cancer cells growth and invasion [52]. A recent report demonstrated that morin hydrate can effectively inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cancer cells metastatic through an Akt/GSK-3β/c-Fos signaling pathway in human MCF-7 breast cancer cells [53]. Naringenin is another naturally occurring plant flavonoid compound linked to three key targets which was found to suppress the migration and invasion of human breast cancer cells of MDA-MB-231 and MCF-7 [54][55][56].…”

uPAR: An Essential Factor for Tumor Development

“…Quercetin has been proven to induce antimetastatic effects in gastric cancer cells by suppressing the uPA/uPAR system via modulation of various associated pathways, including the NF-κb, PKC-δ, ERK1/2, and AMPKα pathways, indicating that uPAR may be a potential target for the treatment of gastric cancer 161 . The plant flavonoid 2',3,4',5,7‑pentahydroxyflavone can effectively inhibit the expression of uPA and uPAR and inhibit TPA-induced metastasis of human breast cancer cells through the Akt/GSK-3β/C-FOS pathway 162 . Moreover, apigenin plays an anti-invasive role by mediating the (ERK1/2, JNK)/AP-1 and (ERK1/2, JNK)/NF-κB signaling pathways to inhibit the expression of uPAR 163 .…”