title: Tetrandrine inhibits migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes through down-regulating the expressions of Rac1, Cdc42, and RhoA GTPases and activation of the PI3K/Akt and JNK signaling pathways.
abstract: Tetrandrine (Tet), the main active constituent of Stephania tetrandra root, has been demonstrated to alleviate adjuvant-induced arthritis in rats. The present study was designed to investigate the effects of Tet on the migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and explore the underlying mechanisms. By using cultures of primary FLS isolated from synoviums of RA patients and cell line MH7A, Tet (0.3, 1 μmol·L(-1)) was proven to significantly impede migration and invasion of RA-FLS, but not cell proliferation. Tet also greatly reduced the activation and expressions of matrix degrading enzymes MMP-2/9, the expression of F-actin and the activation of FAK, which controlled the morphologic changes in migration process of FLS. To identify the key signaling pathways by which Tet exerts anti-migration effect, the specific inhibitors of multiple signaling pathways LY294002, Triciribine, SP600125, U0126, SB203580, and PDTC (against PI3K, Akt, JNK, ERK, p38 MAPK and NF-κB-p65, respectively) were used. Among them, LY294002, Triciribine, and SP600125 were shown to obviously inhibit the migration of MH7A cells. Consistently, Tet was able to down-regulate the activation of Akt and JNK as demonstrated by Western blotting assay. Moreover, Tet could reduce the expressions of migration-related proteins Rho GTPases Rac1, Cdc42, and RhoA in MH7A cells. In conclusion, Tet can impede the migration and invasion of RA-FLS, which provides a plausible explanation for its protective effect on RA. The underlying mechanisms involve the reduction of the expressions of Rac1, Cdc42, and RhoA, inhibition of the activation of Akt and JNK, and subsequent down-regulation of activation and/or expressions of MMP-2/9, F-actin, and FAK.
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Lv
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xian-Yang
authors.initials: XY
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Xia
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China. Electronic address: yuedaicpu@hotmail.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zhifeng-wei@hotmail.com.
authors.forename: Zhi-Feng
authors.initials: ZF
authors.lastname: Wei
mesh_terms: D000818:Animals; D001168:Arthritis; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000517:prevention & control; D044182:Benzylisoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D018517:Plant Roots; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D031607:Stephania / Q000737:chemistry*; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D044182:Benzylisoquinolines; D019869:Phosphatidylinositol 3-Kinases; D010936:Plant Extracts; D017346:Protein Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; C107953:RAC1 protein, human; C066737:RHOA protein, human; C009438:tetrandrine
keywords: Fibroblast-like synoviocytes; Invasion; Migration; Rheumatoid arthritis; Tetrandrine