title: Saponins from the roots of Platycodon grandiflorum suppresses TGFβ1-induced epithelial-mesenchymal transition via repression of PI3K/Akt, ERK1/2 and Smad2/3 pathway in human lung carcinoma A549 cells.
abstract: Transforming growth factor β (TGFβ) is a multifunctional cytokine that induces growth arrest, tissue fibrosis, and epithelial-mesenchymal transition (EMT) through activation of Smad and non-Smad signaling pathways. EMT is the differentiation switch by which polarized epithelial cells differentiate into contractile and motile mesenchymal cells. Our previous studies have shown that saponins from the roots of Platycodon grandiflorum (CKS) have antiinflammatory, antioxidant, antimetastatic, and hepatoprotective effects. In this study, we investigated the inhibitory effect of CKS on TGFβ1-induced alterations characteristic of EMT in human lung carcinoma A549 cells. We found that CKS-treated cells displayed inhibited TGFβ1-mediated E-cadherin downregulation and Vimentin upregulation and also retained epithelial morphology. Furthermore, TGFβ1-increased Snail expression, a repressor of E-cadherin and an inducer of the EMT, was reduced by CKS. CKS inhibited TGFβ1-induced phosphorylation of Akt, ERK1/2, and glycogen synthase kinase-3β (GSK-3β). Inhibition of PI3K/Akt and ERK1/2 also blocked TGFβ1-induced GSK-3β phosphorylation and Snail activation. Furthermore, TGFβ1-increased Snail expression was reduced by selective inhibitors of Akt and ERK1/2. Moreover, CKS treatment attenuated TGFβ1-induced Smad2/3 phosphorylation and upregulated Smad7 expression. These results indicate that pretreatment with the CKS inhibits the TGFβ1-induced EMT through PI3K/Akt, ERK1/2, GSK-3β and Smad2/3 in human lung carcinoma cells.
authors.affiliation: a Department of Toxicology, College of Pharmacy , Chungnam National University , Daejeon , Republic of Korea.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Yong Pil
authors.initials: YP
authors.lastname: Hwang
authors.forename: Hyung Gyun
authors.initials: HG
authors.lastname: Kim
authors.forename: Tilak
authors.initials: T
authors.lastname: Khanal
authors.forename: Minh Truong
authors.initials: MT
authors.lastname: Do
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Jin
authors.forename: Hwa Jeong
authors.initials: HJ
authors.lastname: Han
authors.forename: Hyun Sun
authors.initials: HS
authors.lastname: Lee
authors.forename: Young Chun
authors.initials: YC
authors.lastname: Lee
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Chung
authors.forename: Tae Cheon
authors.initials: TC
authors.lastname: Jeong
authors.forename: Hye Gwang
authors.initials: HG
authors.lastname: Jeong
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015536:Down-Regulation; D063185:Epigenetic Repression; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology; D018517:Plant Roots / Q000737:chemistry; D031238:Platycodon / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D010936:Plant Extracts; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D012503:Saponins; D051899:Smad2 Protein; D051900:Smad3 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3