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.
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.
Department of Orthopedics, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan.
Ko-Hsiu
KH
Lu
Institute of Biochemistry, Microbiology and Immunology, Chung Shang Medical University, Taichung City, Taiwan; Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan.
Pei-Ni
PN
Chen
Institute of Biochemistry, Microbiology and Immunology, Chung Shang Medical University, Taichung City, Taiwan.
Yi-Hsien
YH
Hsieh
Institute of Biochemistry, Microbiology and Immunology, Chung Shang Medical University, Taichung City, Taiwan.
Chin-Yin
CY
Lin
Institute of Biochemistry, Microbiology and Immunology, Chung Shang Medical University, Taichung City, Taiwan.
Fu-Yuan
FY
Cheng
Institute of Biochemistry, Microbiology and Immunology, Chung Shang Medical University, Taichung City, Taiwan.
Peng-Chou
PC
Chiu
Institute and Department of Food Science, Central Taiwan University of Science and Technology, Taichung, Taiwan. Electronic address: scchu@ctust.edu.tw.
Shu-Chen
SC
Chu
Institute of Biochemistry, Microbiology and Immunology, Chung Shang Medical University, Taichung City, Taiwan; Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: csmcysh@csmu.edu.tw.
Yih-Shou
YS
Hsieh
D000293:Adolescent; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D024722:Cardiac Myosins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018994:Myosin Light Chains / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D014408:Biomarkers, Tumor; D005419:Flavonoids; D018994:Myosin Light Chains; C107184:myosin light chain 2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D024722:Cardiac Myosins; D020742:rhoA GTP-Binding Protein; C041477:3-hydroxyflavone
3-Hydroxyflavone; FAK-Src; MEK/ERK; Metastasis; Osteosarcoma; RhoA/MLC2