Abstract
In spite of numerous advances, the 5-year survival rate for head and neck squamous cell cancer has remained largely stagnant and few new anti-tumor drugs have been developed. PCH4, a derivative of n-butylidenephthalide, has been investigated for its anti-tumor effects on oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the anti-tumor mechanism of a potential target gene, Nur77, in OSCC cells, which can be induced by PCH4 treatment. Data show that PCH4 promoted Nur77 translocation from the nucleus to the cytoplasm and induced cell apoptosis in OSCC cells. When Nur77 translocation was blocked, the degree of tumor apoptosis caused by PCH4 was significantly inhibited (p < 0.05). Within the MAPK pathway, PCH4 only induced JNK phosphorylation. Furthermore, treatment with a JNK inhibitor significantly reduced PCH4-induced apoptosis (p < 0.05) and decreased PCH4-induced Nur77 expression (p < 0.05). In a xenograft animal model, administration of PCH4 also showed anti-tumor effects. We have demonstrated that OSCC cells are sensitive to PCH4 and that Nur77 protein translocation from the nucleus to the cytoplasm might be associated with the induction of apoptosis by PCH4. These results indicate that PCH4 may serve as a potential anti-tumor drug for OSCC therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Benzofurans / pharmacology*
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Carcinoma, Squamous Cell / drug therapy*
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Ethylamines / pharmacology*
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Female
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Humans
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mouth Neoplasms / drug therapy*
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Mouth Neoplasms / genetics
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Mouth Neoplasms / metabolism
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Mouth Neoplasms / pathology
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Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
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Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
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Phosphorylation
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Phthalic Anhydrides / pharmacology*
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Protein Kinase Inhibitors / pharmacology
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RNA, Messenger / metabolism
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Time Factors
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Tumor Burden / drug effects
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Up-Regulation
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Benzofurans
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Ethylamines
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N-(2-(dimethylamino)ethyl)-2-(3-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenoxy)acetamide
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NR4A1 protein, human
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Phthalic Anhydrides
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Protein Kinase Inhibitors
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RNA, Messenger
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JNK Mitogen-Activated Protein Kinases
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butylidenephthalide