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

Cheng Wei Lin, Shing Chuan Shen, Chih Chiang Chien, Liang Yo Yang, Lin Ting Shia, Yen Chou Chen

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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)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.

Original languageEnglish
Pages (from-to)472-481
Number of pages10
JournalJournal of Cellular Physiology
Volume225
Issue number2
DOIs
Publication statusPublished - 2010

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Extracellular Signal-Regulated MAP Kinases
Tetradecanoylphorbol Acetate
Glioblastoma
Matrix Metalloproteinases
Protein Kinase C
Cell Movement
Acetates
Chemical activation
Flavonoids
Luteolin
Phosphorylation
Enzyme Activation
Protein C Inhibitor
JNK Mitogen-Activated Protein Kinases
Enzyme activity
Protein Transport
Structure-Activity Relationship
Protein Kinase Inhibitors
Nuclear Proteins
Luciferases

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology
  • Medicine(all)

Cite this

@article{3eb30f6c7554480cbab1d3d5f1362966,
title = "12-O-tetradecanoylphorbol-13-acetate-induced invasion/migration of glioblastoma cells through activating PKCα/ERK/NF-κB-dependent MMP-9 expression",
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)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.",
author = "Lin, {Cheng Wei} and Shen, {Shing Chuan} and Chien, {Chih Chiang} and Yang, {Liang Yo} and Shia, {Lin Ting} and Chen, {Yen Chou}",
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journal = "Journal of Cellular Physiology",
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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

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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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