Silibinin Inhibits Cell Invasion Through Inactivation of Both PI3K-Akt and MAPK Signaling Pathways

Chem Biol Interact. 2005 Oct 20;156(2-3):141-50. doi: 10.1016/j.cbi.2005.08.005.

Abstract

Silibinin, isolated from Silybum marianum, has been known for its hepatoprotective properties and recent studies have revealed its antiproliferative and apoptotic effects on several cancer cells. An inhibitory effect of silibinin on tumor invasion and matrix metalloproteinase-2 (MMP-2) and urokinasetype plasminogen activator (u-PA) activities in culture medium has been observed in our previous study and the impacts of silibinin on enzyme activities of MMPs, u-PA, mitogen-activated protein kinase (MAPK) and Akt in A549 cells were continued to explore in this study. Our results showed that silibinin exerted an inhibitory effect on the phosphorylation of Akt, as well as extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are the members of the MAPK family involved in the up-regulation of MMPs or u-PA, while no effects on the activities of p38(MAPK) and stress-activated protein kinase/c-Jun N-terminal kinase were observed. A treatment with silibinin to A549 cells also led to a dose-dependent inhibition on the activation of NF-kappaB, c-Jun and c-Fos. Additionally, the treatment of inhibitors specific for MEK (U0126) or PI3K (LY294002) to A549 cells could result in a reduced expression of MMP-2 and u-PA concomitantly with a marked inhibition on cell invasion. These findings suggested that the inhibition on MMP-2 and u-PA expression by silibinin may be through a suppression on ERK1/2 or Akt phosphorylation, which in turn led to the reduced invasiness of the cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Butadienes / pharmacology
  • Cell Line, Tumor / drug effects
  • Cell Movement / drug effects*
  • Chromones / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / enzymology
  • MAP Kinase Signaling System / drug effects
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase Inhibitors
  • Milk Thistle / chemistry*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Morpholines / pharmacology
  • Nitriles / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphorylation
  • Plant Extracts / pharmacology
  • Silybin
  • Silymarin / pharmacology
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors
  • Urokinase-Type Plasminogen Activator / biosynthesis

Substances

  • Anticarcinogenic Agents
  • Butadienes
  • Chromones
  • Enzyme Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • Morpholines
  • Nitriles
  • Phosphoinositide-3 Kinase Inhibitors
  • Plant Extracts
  • Silymarin
  • U 0126
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Silybin
  • Mitogen-Activated Protein Kinases
  • Urokinase-Type Plasminogen Activator
  • Matrix Metalloproteinase 2