3-Hydroxyflavone inhibits human osteosarcoma U2OS and 143B cells metastasis by affecting EMT and repressing u-PA/MMP-2 via FAK-Src to MEK/ERK and RhoA/MLC2 pathways and reduces 143B tumor growth in vivo. (November 2016)

• Record Type: Journal Article
• Authors: Lu, Ko-Hsiu; Chen, Pei-Ni; Hsieh, Yi-Hsien; Lin, Chin-Yin; Cheng, Fu-Yuan; Chiu, Peng-Chou; Chu, Shu-Chen; Hsieh, Yih-Shou
• Is Part Of: Food and chemical toxicology. Volume 97(2016)
• Page Start: 177
• Page End: 186
• Publication Date: 2016-11
• Subjects: FAK-Src -- MEK/ERK -- Metastasis -- Osteosarcoma -- RhoA/MLC2 -- 3-Hydroxyflavone; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2016.09.006
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Many natural flavonoids have cytostatic and apoptotic properties; however, we little know whether the effect of synthetic 3-hydroxyflavone on metastasis and tumor growth of human osteosarcoma. Here, we tested the hypothesis that 3-hydroxyflavone suppresses human osteosarcoma cells metastasis and tumor growth. 3-hydroxyflavone, up to 50 μM without cytotoxicity, inhibited U2OS and 143B cells motility, invasiveness and migration by reducing matrix metalloproteinase (MMP)-2 and urokinase-type plasminogen activator (u-PA) and also impaired cell adhesion to gelatin. 3-hydroxyflavone significantly reduced p-focal adhesion kinase (FAK) Tyr397, p-FAK Tyr925, p-steroid receptor coactivator (Src), p-mitogen/extracellular signal-regulated kinase (MEK)1/2, p-myosin light chain (MLC)2 Ser19, epithelial cell adhesion molecule, Ras homolog gene family (Rho)A and fibronectin expressions. 3-hydroxyflavone also affected the epithelial-mesenchymal transition (EMT) by down-regulating expressions of Vimentin and α-catenin with activation of the transcription factor Slug. In nude mice xenograft model and tail vein injection model showed that 3-hydroxyflavone reduced 143B tumor growth and lung metastasis. 3-hydroxyflavone possesses the anti-metastatic activity of U2OS and 143B cells by affecting EMT and repressing u-PA/MMP-2 via FAK-Src to MEK/ERK and RhoA/MLC2 pathways and suppresses 143B tumor growth in vivo . This may lead to clinical trials of osteosarcoma chemotherapy to confirm the promising result in the future. Graphical abstract: Highlights: 3-Hydroxyflavone inhibits U2OS and 143B cells migration, invasiveness and motility. 3-Hydroxyflavone inhibits MMP-2 of U2OS and 143B cells and u-PA of U2OS cells. 3-Hydroxyflavone decreases FAK, Src, MEK/ERK and MLC2 phosphorylation. 3-Hydroxyflavone affects EMT of U2OS and 143B cells. 3-Hydroxyflavone reduces 143B tumor growth in vivo .