morin and Neoplasm-Metastasis

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)‑induced 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.

Topics: Breast Neoplasms; Cell Movement; Cell Survival; Flavonoids; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 beta; Humans; MCF-7 Cells; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-fos; Signal Transduction; Tetradecanoylphorbol Acetate

Morin, a flavonoid found in figs and other Moraceae, displays a variety of biological actions, such as anti-oxidant, anti-inflammatory and anti-carcinogenic. However, the anticancer effects of morin and in particular its anti-metastatic effects are not well known. Therefore, in the present study, we investigated the anticancer effects of morin on highly metastatic human breast cancer cells. Our results showed that morin significantly inhibited the colony forming ability of highly metastatic MDA-MB‑231 breast cancer cells from low doses (50 µM) without cytotoxicity. In addition, morin changed MDA-MB‑231 cell morphology from mesenchymal shape to epithelial shape and inhibited the invasion of MDA-MB‑231 cells in a dose-dependent manner. Morin decreased matrix metalloproteinase-9 (MMP-9) secretion and expression of the mesenchymal marker N-cadherin of MDA-MB‑231 cells, suggesting that morin might suppress the EMT process. Furthermore, morin significantly decreased the phosphorylation of Akt, and inhibition of the Akt pathway significantly reduced MDA-MB‑231 invasion. In an in vivo xenograft mouse model, morin suppressed MDA-MB‑231 cancer cell progression. Taken together, our findings suggest that morin exhibits an inhibitory effect on the cancer progression and EMT process of highly metastatic breast cancer cells at least in part through inhibiting Akt activation. This study provides evidence that morin may have anticancer effects against metastatic breast cancer.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Epithelial-Mesenchymal Transition; Female; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Signaling System; Mice; Mice, Nude; Moraceae; Neoplasm Invasiveness; Neoplasm Metastasis; Plant Extracts; Xenograft Model Antitumor Assays