TY - JOUR
T1 - 12-O-tetradecanoylphorbol-13-acetate-induced invasion/migration of glioblastoma cells through activating PKCα/ERK/NF-κB-dependent MMP-9 expression
AU - Lin, Cheng Wei
AU - Shen, Shing Chuan
AU - Chien, Chih Chiang
AU - Yang, Liang Yo
AU - Shia, Lin Ting
AU - Chen, Yen Chou
PY - 2010/11
Y1 - 2010/11
N2 - 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)α from the cytosol to membranes, and migration of GBM8401 elicited by TPA was suppressed by adding the PKCα 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-κB protein p65 nuclear translocation and IκBα protein phosphorylation with increased NF-κB-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 PKCα siRNA specifically reduced PKCα protein expression with blocking TPA-induced MMP-9 activation and migration. Additionally, suppression of TPA-induced PKCα/ERK/NK-κB 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 PKCα/ERK/NF-κB activation is first demonstrated herein.
AB - 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)α from the cytosol to membranes, and migration of GBM8401 elicited by TPA was suppressed by adding the PKCα 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-κB protein p65 nuclear translocation and IκBα protein phosphorylation with increased NF-κB-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 PKCα siRNA specifically reduced PKCα protein expression with blocking TPA-induced MMP-9 activation and migration. Additionally, suppression of TPA-induced PKCα/ERK/NK-κB 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 PKCα/ERK/NF-κB activation is first demonstrated herein.
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U2 - 10.1002/jcp.22226
DO - 10.1002/jcp.22226
M3 - Article
C2 - 20458747
AN - SCOPUS:77956501267
SN - 0021-9541
VL - 225
SP - 472
EP - 481
JO - Journal of Cellular Physiology
JF - Journal of Cellular Physiology
IS - 2
ER -