title: Nobiletin inhibits human osteosarcoma cells metastasis by blocking ERK and JNK-mediated MMPs expression.
abstract: Nobiletin, a polymethoxyflavone, has a few pharmacological activities, including anti-inflammation and anti-cancer effects. However, its effect on human osteosarcoma progression remains uninvestigated. Therefore, we examined the effectiveness of nobiletin against cellular metastasis of human osteosarcoma and the underlying mechanisms. Nobiletin, up to 100 μM without cytotoxicity, significantly decreased motility, migration and invasion as well as enzymatic activities, protein levels and mRNA expressions of matrix metalloproteinase (MMP)-2 and MMP-9 in U2OS and HOS cells. In addition to inhibition of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), the inhibitory effect of nobiletin on the DNA-binding activity of the transcription factor nuclear factor-kappa B (NF-κB), cAMP response element-binding protein (CREB), and specificity protein 1 (SP-1) in U2OS and HOS cells. Co-treatment with ERK and JNK inhibitors and nobiletin further reduced U2OS cells migration and invasion. These results indicated that nobiletin inhibits human osteosarcoma U2OS and HOS cells motility, migration and invasion by down-regulating MMP-2 and MMP-9 expressions via ERK and JNK pathways and through the inactivation of downstream NF-κB, CREB, and SP-1. Nobiletin has the potential to serve as an anti-metastatic agent for treating osteosarcoma.
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
authors.forename: Hsin-Lin
authors.initials: HL
authors.lastname: Cheng
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.|Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan.
authors.forename: Ming-Ju
authors.initials: MJ
authors.lastname: Hsieh
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
authors.forename: Jia-Sin
authors.initials: JS
authors.lastname: Yang
authors.affiliation: Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
authors.forename: Chiao-Wen
authors.initials: CW
authors.lastname: Lin
authors.affiliation: School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Ko-Haung
authors.initials: KH
authors.lastname: Lue
authors.affiliation: School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Orthopedics, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
authors.forename: Ko-Hsiu
authors.initials: KH
authors.lastname: Lu
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness; D012516:Osteosarcoma / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D047309:Flavones; C008661:nobiletin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: CREB; MMP; SP-1; metastasis; nobiletin