Plumbagin inhibits TPA-induced MMP-2 and u-PA expressions by reducing binding activities of NF-kappaB and AP-1 via ERK signaling pathway in A549 human lung cancer cells

Mol Cell Biochem. 2010 Feb;335(1-2):181-93. doi: 10.1007/s11010-009-0254-7. Epub 2009 Sep 21.

Abstract

This study first investigates the anti-metastatic effect of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMPs and u-PA expressions in human lung cancer cells, A549. First, the result demonstrated plumbagin could inhibit TPA induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and Boyden chamber assay. Data also showed plumbagin could inhibit the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) involved in the down-regulating enzyme activities, protein and messenger RNA levels of matrix metalloproteinase-2 (MMP-2), and urokinase-type plasminogen activator (u-PA) induced by TPA. Next, plumbagin also strongly inhibited TPA-induced phosphorylation and degradation of inhibitor of kappaBalpha (IkappaBalpha), and the nuclear levels of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun. Also, a dose-dependent inhibition on the binding abilities of NF-kappaB and activator protein-1 (AP-1) by plumbagin treatment was further observed. Further, the treatment of specific inhibitor for ERK (U0126) to A549 cells could inhibit TPA-induced MMP-2 and u-PA expressions along with an inhibition on cell invasion and migration. Presented data reveals that plumbagin is a novel, effective, anti-metastatic agent that functions by down-regulating MMP-2 and u-PA gene expressions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase Inhibitors*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • NF-kappa B / metabolism*
  • Naphthoquinones / pharmacology*
  • Phosphorylation
  • Signal Transduction*
  • Tetradecanoylphorbol Acetate / pharmacology*
  • Transcription Factor AP-1 / metabolism*
  • Urokinase-Type Plasminogen Activator / metabolism*

Substances

  • Matrix Metalloproteinase Inhibitors
  • NF-kappa B
  • Naphthoquinones
  • Transcription Factor AP-1
  • Mitogen-Activated Protein Kinase 3
  • Urokinase-Type Plasminogen Activator
  • Matrix Metalloproteinase 2
  • Tetradecanoylphorbol Acetate
  • plumbagin