title: Expression of Nur77 induced by an n-butylidenephthalide derivative promotes apoptosis and inhibits cell growth in oral squamous cell carcinoma.
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.
authors.affiliation: School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.
authors.forename: Po Yen
authors.initials: PY
authors.lastname: Liu
authors.forename: Jim Jinn-Chyuan
authors.initials: JJ
authors.lastname: Sheu
authors.forename: Po Cheng
authors.initials: PC
authors.lastname: Lin
authors.forename: Cheng Tung
authors.initials: CT
authors.lastname: Lin
authors.forename: Ya Jung
authors.initials: YJ
authors.lastname: Liu
authors.forename: Li Ing
authors.initials: LI
authors.lastname: Ho
authors.forename: Li Fu
authors.initials: LF
authors.lastname: Chang
authors.forename: Wan Chen
authors.initials: WC
authors.lastname: Wu
authors.forename: Syue Rong
authors.initials: SR
authors.lastname: Chen
authors.forename: Jay
authors.initials: J
authors.lastname: Chen
authors.forename: Yeu Chern
authors.initials: YC
authors.lastname: Harn
authors.forename: Shinn Zong
authors.initials: SZ
authors.lastname: Lin
authors.forename: Chang Hai
authors.initials: CH
authors.lastname: Tsai
authors.forename: Tzyy Wen
authors.initials: TW
authors.lastname: Chiou
authors.forename: Horng Jyh
authors.initials: HJ
authors.lastname: Harn
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005021:Ethylamines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010796:Phthalic Anhydrides / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D005021:Ethylamines; C558309:N-(2-(dimethylamino)ethyl)-2-(3-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenoxy)acetamide; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010796:Phthalic Anhydrides; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D048031:JNK Mitogen-Activated Protein Kinases; C026105:butylidenephthalide
references.citation: Mol Cell Biol. 2003 Dec;23(23):8651-67
references.pmid: 14612408
references.citation: Cell Death Differ. 2000 Mar;7(3):262-71
references.pmid: 10745271
references.citation: Mol Reprod Dev. 2008 May;75(5):931-9
references.pmid: 18163434
references.citation: Mol Pharmacol. 2008 Oct;74(4):1046-58
references.pmid: 18577687
references.citation: World J Gastroenterol. 2002 Jun;8(3):446-50
references.pmid: 12046067
references.citation: J Neurochem. 2008 Aug;106(3):1017-26
references.pmid: 18419761
references.citation: Cell. 2004 Feb 20;116(4):527-40
references.pmid: 14980220
references.citation: CA Cancer J Clin. 2006 Mar-Apr;56(2):106-30
references.pmid: 16514137
references.citation: Int J Cancer. 1992 Dec 2;52(6):867-72
references.pmid: 1459726
references.citation: Oncogene. 1996 Apr 18;12(8):1755-65
references.pmid: 8622896
references.citation: Cancer Res. 1998 Aug 15;58(16):3620-6
references.pmid: 9721870
references.citation: Science. 2000 Aug 18;289(5482):1159-64
references.pmid: 10947977
references.citation: J Mol Endocrinol. 2009 Feb;42(2):119-29
references.pmid: 18987158
references.citation: J Neurochem. 2006 Nov;99(4):1251-62
references.pmid: 16987298
references.citation: Oncogene. 1992 May;7(5):927-33
references.pmid: 1570156
references.citation: Carcinogenesis. 2004 Aug;25(8):1467-75
references.pmid: 15016657
references.citation: Oncogene. 2006 Aug 7;25(34):4725-43
references.pmid: 16892086
references.citation: J Biol Chem. 2004 Nov 26;279(48):50097-101
references.pmid: 15448159
references.citation: Oncogene. 2006 May 18;25(21):2974-86
references.pmid: 16434970
references.citation: Expert Opin Ther Targets. 2007 Jan;11(1):69-79
references.pmid: 17150035
references.citation: J Agric Food Chem. 2010 Feb 10;58(3):1630-8
references.pmid: 20043672
references.citation: Cytometry. 1998 Jan 1;31(1):1-9
references.pmid: 9450519
references.citation: Mol Endocrinol. 2002 Jul;16(7):1638-51
references.pmid: 12089357