title: Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-β1-induced epithelial-mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance.
abstract: The epithelial-mesenchymal transition (EMT) is a pivotal cellular process during which epithelial polarized cells become motile mesenchymal-appearing cells, which, in turn, promotes the metastatic potential of cancer. Ginseng is a perennial plant belonging to the genus Panax that exhibits a wide range of pharmacological and physiological activities. Ginsenosides 20-Rg3, which is the active component of ginseng, has various medical effects, such as anti-tumorigenic, anti-angiogenesis, and anti-fatiguing activities. In addition, ginsenosides 20(S)-Rg3 and 20(R)-Rg3 are epimers, and this epimerization is produced by steaming. However, the possible role of 20(S)-Rg3 and 20(R)-Rg3 in the EMT is unclear. We investigated the effect of 20(S)-Rg3 and 20(R)-Rg3 on the EMT. Transforming growth factor-beta 1 (TGF-β1) induces the EMT to promote lung adenocarcinoma migration, invasion, and anoikis resistance. To understand the repressive role of 20(S)-Rg3 and 20(R)-Rg3 in lung cancer migration, invasion, and anoikis resistance, we investigated the potential use of 20(S)-Rg3 and 20(R)-Rg3 as inhibitors of TGF-β1-induced EMT development in A549 lung cancer cells in vitro. Here, we show that 20(R)-Rg3, but not 20(S)-Rg3, markedly increased expression of the epithelial marker E-cadherin and repressed Snail upregulation and expression of the mesenchymal marker vimentin during initiation of the TGF-β1-induced EMT. 20(R)-Rg3 also inhibited the TGF-β1-induced increase in cell migration, invasion, and anoikis resistance of A549 lung cancer cells. Additionally, 20(R)-Rg3 markedly inhibited TGF-β1-regulated matrix metalloproteinase-2 and activation of Smad2 and p38 mitogen activated protein kinase. Taken together, our findings provide new evidence that 20(R)-Rg3 suppresses lung cancer migration, invasion, and anoikis resistance in vitro by inhibiting the TGF-β1-induced EMT.
authors.affiliation: Natural Medicine Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, South Korea.
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Bu-Nam
authors.initials: BN
authors.lastname: Jeon
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, South Korea; Department of Pharmacology, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, South Korea; Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Kunhong
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, Cheil General Hospital and Women's Healthcare Center, Kwandong University College of Medicine, Seoul, South Korea.
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Kim
authors.affiliation: Natural Medicine Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, South Korea.
authors.forename: Jungyeob
authors.initials: J
authors.lastname: Ham
authors.affiliation: University of Ulsan, Department of Surgery, Gangneung Asan Hospital, Gangneung, Gangwon-do, South Korea.
authors.forename: Hyuk Jai
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: College of Korean Medicine, Gachon University, Seongnam, South Korea.
authors.forename: Ki Sung
authors.initials: KS
authors.lastname: Kang
authors.affiliation: Laboratory of Molecular Oncology, Cheil General Hospital & Women's Healthcare Center, Kwandong University College of Medicine, Seoul, South Korea. Electronic address: drug9054@naver.com.
authors.forename: Hyeonseok
authors.initials: H
authors.lastname: Ko
mesh_terms: D023102:Anoikis / Q000187:drug effects*; D015153:Blotting, Western; D015820:Cadherins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D036145:Ginsenosides / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D051899:Smad2 Protein / Q000378:metabolism; D013237:Stereoisomerism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014746:Vimentin / Q000096:biosynthesis; D014945:Wound Healing / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015820:Cadherins; D036145:Ginsenosides; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D014746:Vimentin; C097367:ginsenoside Rg3; D012313:RNA; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2
keywords: Epithelial–mesenchymal transition (EMT); Ginsenoside 20(R)-Rg3; Lung cancer; Metastasis; Transforming growth factor-beta 1 (TGF-β1)