Abstract
Notch signaling pathway plays critical roles in human cancers, including osteosarcoma, suggesting that the discovery of specific agents targeting Notch would be extremely valuable for osteosarcoma. Our previous studies have shown that diallyl trisulfide (DATS) inhibits proliferation of osteosarcoma cells by triggering cell cycle arrest and apoptosis in vitro. However, the underlying mechanism is still unclear. In this study, we found that DATS suppressed cell survival, wound-healing capacity, invasion and angiogenesis in osteosarcoma cells. These effects were associated with decreased expression of Notch-1 and its downstream genes, such as vascular endothelial growth factor and matrix metalloproteinases, as well as increased expression of a panel of tumor-suppressive microRNAs (miRNAs), including miR-34a, miR-143, miR-145 and miR-200b/c that are typically lost in osteosarcoma. We also found that reexpression of miR-34a and miR-200b by transfection led to reduced expression of Notch-1, resulting in the inhibition of osteosarcoma cell proliferation, invasion and angiogenesis. These results clearly suggest that DATS inhibited osteosarcoma growth and aggressiveness via a novel mechanism targeting a Notch-miRNA regulatory circuit. Our data provide the first evidence that the downregulation of Notch-1 and reexpression of miRNAs by DATS may be an effective approach for the treatment of osteosarcoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Allyl Compounds / pharmacology*
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Antineoplastic Agents / pharmacology
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Movement / drug effects
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Cell Proliferation / drug effects*
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Cell Survival / drug effects
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Collagen / metabolism
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Culture Media, Conditioned
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Drug Combinations
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Gene Expression Regulation, Neoplastic
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Human Umbilical Vein Endothelial Cells
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Humans
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Laminin / metabolism
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 2 / metabolism
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MicroRNAs / genetics
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MicroRNAs / metabolism
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Neoplasm Invasiveness / prevention & control*
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Neovascularization, Pathologic / prevention & control*
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Osteosarcoma / metabolism
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Osteosarcoma / pathology*
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Proteoglycans / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Signal Transduction / drug effects
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Sulfides / pharmacology*
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Transcription Factor HES-1
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Transfection
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Allyl Compounds
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Antineoplastic Agents
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Basic Helix-Loop-Helix Transcription Factors
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Culture Media, Conditioned
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Drug Combinations
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Homeodomain Proteins
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Laminin
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MIRN34 microRNA, human
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MicroRNAs
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NOTCH1 protein, human
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Proteoglycans
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RNA, Small Interfering
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Receptor, Notch1
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Sulfides
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Transcription Factor HES-1
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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diallyl trisulfide
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matrigel
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HES1 protein, human
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Collagen
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MMP2 protein, human
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Matrix Metalloproteinase 2