Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 225, Issue 2, Pages 472-481Publisher
WILEY
DOI: 10.1002/jcp.22226
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Funding
- National Science Council of Taiwan [NSC96-2320-B-038-031-MY3, 98-2320-B-038-002-MY3]
- Taipei Medical University-Shuang Ho Hospital [98TMU-SHH-01-2]
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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 PKC alpha 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-kappa B protein p65 nuclear translocation and I kappa B alpha protein phosphorylation with increased NF-kappa B-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 PKC alpha siRNA specifically reduced PKC alpha protein expression with blocking TPA-induced MMP-9 activation and migration. Additionally, suppression of TPA-induced PKC alpha/ERK/NK-kappa B 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 PKC alpha/ERK/NF-kappa B activation is first demonstrated herein. J. Cell. Physiol. 225: 472-481, 2010. (C) 2010 Wiley-Liss, Inc.
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