20( S)-Ginsenoside Rg3 Inhibits Lung Cancer Cell Proliferation by Targeting EGFR-Mediated Ras/Raf/MEK/ERK Pathway

Am J Chin Med. 2021;49(3):753-765. doi: 10.1142/S0192415X2150035X. Epub 2021 Feb 25.

Abstract

Lung cancer is the leading cause of cancer death in the world and classified into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). As tyrosine kinase inhibitors (TKIs), several triterpenoid saponins can target to epidermal growth factor receptor (EGFR), a widely used molecular therapeutic target, to exhibit remarkable anti-proliferative activities in cancer cells. As one of triterpenoid saponins, 20([Formula: see text])-ginsenoside Rg3 [20([Formula: see text])-Rg3] was confirmed to be an EGFR-TKI in this work. According to the quantitative real-time reverse transcription-PCR (qRT-PCR) and immunoblotting analysis, 20([Formula: see text])-Rg3 was certified to play a key role on EGFR/Ras/Raf/MEK/ERK signal pathway regulation. Our data demonstrated that 20([Formula: see text])-Rg3 might block the cell cycle at the G0/G1 phase by downregulating CDK2, Cyclin A2, and Cyclin E1. Molecular docking suggested that the combination of both hydrophobic and hydrogen-bonding interactions may help stabilizing the 20([Formula: see text])-Rg3-EGFR binding. Furthermore, their binding stability was assessed by molecular dynamics simulation. Taken together, these data provide the evidence that 20([Formula: see text])-Rg3 could prohibit A549 cell proliferation, probably by arresting the cell cycle at the G0/G1 phase via the EGFR/Ras/Raf/MEK/ERK pathway.

Keywords: 20([Formula: see text])-Ginsenoside Rg3; Binding Interaction; Cell Cycle; Cell Proliferation; Epidermal Growth Factor Receptor.

MeSH terms

  • A549 Cells
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Cycle / genetics
  • Cell Proliferation / genetics*
  • ErbB Receptors / metabolism
  • Ginsenosides / pharmacology*
  • Ginsenosides / therapeutic use
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology*
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / genetics*
  • Molecular Targeted Therapy
  • Phytotherapy
  • raf Kinases / metabolism*
  • ras Proteins / metabolism*

Substances

  • Ginsenosides
  • ginsenoside Rg3
  • EGFR protein, human
  • ErbB Receptors
  • raf Kinases
  • ras Proteins