Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-β1-induced epithelial-mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance

Toxicology. 2014 Aug 1:322:23-33. doi: 10.1016/j.tox.2014.04.002. Epub 2014 May 2.

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.

Keywords: Epithelial–mesenchymal transition (EMT); Ginsenoside 20(R)-Rg3; Lung cancer; Metastasis; Transforming growth factor-beta 1 (TGF-β1).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anoikis / drug effects*
  • Blotting, Western
  • Cadherins / biosynthesis
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Enzyme Activation / drug effects
  • Epithelial-Mesenchymal Transition / drug effects*
  • Ginsenosides / chemistry
  • Ginsenosides / pharmacology*
  • Humans
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / pathology*
  • Matrix Metalloproteinase 2 / metabolism
  • Neoplasm Invasiveness / prevention & control*
  • RNA / biosynthesis
  • RNA / isolation & purification
  • Real-Time Polymerase Chain Reaction
  • Smad2 Protein / metabolism
  • Stereoisomerism
  • Transforming Growth Factor beta1 / antagonists & inhibitors*
  • Transforming Growth Factor beta1 / pharmacology
  • Vimentin / biosynthesis
  • Wound Healing / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cadherins
  • Ginsenosides
  • SMAD2 protein, human
  • Smad2 Protein
  • Transforming Growth Factor beta1
  • Vimentin
  • ginsenoside Rg3
  • RNA
  • p38 Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 2