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.

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.

• Authors: Ko-Hsiu Lu, Pei-Ni Chen, Yi-Hsien Hsieh, Chin-Yin Lin, Fu-Yuan Cheng, Peng-Chou Chiu, Shu-Chen Chu, Yih-Shou Hsieh
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 97 Pg. 177-186 (Nov 2016) ISSN: 1873-6351 [Electronic] England
• PMID: 27600294 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Flavonoids
• Myosin Light Chains
• myosin light chain 2
• Focal Adhesion Protein-Tyrosine Kinases
• src-Family Kinases
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase 1
• Urokinase-Type Plasminogen Activator
• Matrix Metalloproteinase 2
• Cardiac Myosins
• rhoA GTP-Binding Protein
• 3-hydroxyflavone

Topics

• Adolescent
• Animals
• Apoptosis (drug effects)
• Biomarkers, Tumor (metabolism)
• Blotting, Western
• Bone Neoplasms (metabolism, pathology, prevention & control)
• Cardiac Myosins (metabolism)
• Cell Adhesion (drug effects)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Child
• Epithelial-Mesenchymal Transition (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Flavonoids (pharmacology)
• Focal Adhesion Protein-Tyrosine Kinases (metabolism)
• Humans
• Immunoenzyme Techniques
• MAP Kinase Kinase 1 (metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Myosin Light Chains (metabolism)
• Osteosarcoma (metabolism, prevention & control, secondary)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured
• Urokinase-Type Plasminogen Activator (metabolism)
• Xenograft Model Antitumor Assays
• rhoA GTP-Binding Protein (metabolism)
• src-Family Kinases (metabolism)