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12-O-tetradecanoylphorbol-13-acetate-induced invasion/migration of glioblastoma cells through activating PKCalpha/ERK/NF-kappaB-dependent MMP-9 expression

J Cell Physiol. 2010 Nov;225(2):472-81. doi: 10.1002/jcp.22226.

Abstract

An increase in MMP-9 gene expression and enzyme activity with stimulating the migration of GBM8401 glioma cells via wound healing assay by 12-O-tetradecanoylphorbol-13-acetate (TPA) was detected in glioblastoma cells GBM8401. TPA-induced translocation of protein kinase C (PKC)alpha from the cytosol to membranes, and migration of GBM8401 elicited by TPA was suppressed by adding the PKCalpha inhibitors, GF109203X and H7. Activation of extracellular signal-regulated kinase (ERK) and c-Jun-N-terminal kinase (JNK) by TPA was identified, and TPA-induced migration and MMP-9 activity was significantly blocked by ERK inhibitor PD98059 and U0126, but not JNK inhibitor SP600125. Activation of NF-kappaB protein p65 nuclear translocation and IkappaBalpha protein phosphorylation with increased NF-kappaB-directed luciferase activity by TPA were observed, and these were blocked by the PD98059 and IkB inhibitor BAY117082 accompanied by reducing migration and MMP-9 activity induced by TPA in GBM8401 cells. Transfection of GBM8401 cells with PKCalpha siRNA specifically reduced PKCalpha protein expression with blocking TPA-induced MMP-9 activation and migration. Additionally, suppression of TPA-induced PKCalpha/ERK/NK-kappaB activation, migration, and MMP-9 activation by flavonoids including kaempferol (Kae; 3,5,7,4'-tetrahydroxyflavone), luteolin (Lut; 5,7,3'4'-tetrahydroxyflavone), and wogonin (Wog; 5,7-dihydroxy-8-methoxyflavone) was demonstrated, and structure-activity relationship (SAR) studies showed that hydroxyl (OH) groups at C4' and C8 are critical for flavonoids' action against MMP-9 enzyme activation and migration/invasion of glioblastoma cells elicited by TPA. Application of flavonoids to prevent the migration/invasion of glioblastoma cells through blocking PKCalpha/ERK/NF-kappaB activation is first demonstrated herein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogens / toxicity
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Flavonoids / chemistry
  • Flavonoids / pharmacology
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / metabolism*
  • Humans
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism
  • Matrix Metalloproteinase 9 / metabolism*
  • Molecular Structure
  • NF-kappa B / metabolism*
  • Neoplasm Invasiveness
  • Protein Kinase C-alpha / metabolism*
  • RNA Interference
  • Tetradecanoylphorbol Acetate / toxicity*

Substances

  • Carcinogens
  • Flavonoids
  • NF-kappa B
  • Protein Kinase C-alpha
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 4
  • Matrix Metalloproteinase 9
  • Tetradecanoylphorbol Acetate