title: Oroxylin A inhibits matrix metalloproteinase-2/9 expression and activation by up-regulating tissue inhibitor of metalloproteinase-2 and suppressing the ERK1/2 signaling pathway.
abstract: Matrix metalloproteinases (MMPs) play important roles in the invasion and migration of cancer cells. In this study, we used in vitro and in vivo assays to examine the inhibitory effects of oroxylin A, one of the main bioactive flavonoid extracted from Scutellaria radix, on the human breast carcinoma cell MDA-MB-231 invasion and migration. We found that oroxylin A can suppress cell adhesion, invasion and migration in a concentration-dependent manner. Moreover, oroxylin A led to the reduction of the activity and expression levels of MMP-2 and MMP-9 in gelatin zymography, real-time PCR and western blotting analysis. Further elucidation of the mechanism revealed that oroxylin A increased the expression of tissue inhibitor of metalloproteinase-2 (TIMP-2), the endogenous inhibitor of MMP-2, and repressed the phorbol-12-myristate-13-acetate (PMA)-induced translocation of protein kinase Cδ (PKCδ), phosphorylation of extracellular signal-regulated kinase (ERK1/2) and binding activity of the transcription factor activator protein-1 (AP-1) which are upstream signaling molecules in MMP-9 expression. Our results also indicated that oroxylin A inhibited the lung metastasis of murine melanoma cell B16-F10 in vivo. Therefore, we proposed that oroxylin A might be developed as a therapeutic potential candidate for the treatment of cancer metastasis.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Lu
authors.forename: Na
authors.initials: N
authors.lastname: Lu
authors.forename: Chenglin
authors.initials: C
authors.lastname: Li
authors.forename: Fanni
authors.initials: F
authors.lastname: Li
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.forename: Biqi
authors.initials: B
authors.lastname: Lin
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D018517:Plant Roots / Q000737:chemistry; D060888:Real-Time Polymerase Chain Reaction; D031364:Scutellaria baicalensis / Q000737:chemistry; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis*; D014158:Transcription, Genetic; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; D061965:Matrix Metalloproteinase Inhibitors; D019716:Tissue Inhibitor of Metalloproteinase-2; C080669:5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9