Kalopanaxsaponin A inhibits PMA-induced invasion by reducing matrix metalloproteinase-9 via PI3K/Akt- and PKCδ-mediated signaling in MCF-7 human breast cancer cells

Sun Kyu Park, Young Sun Hwang, Kwang Kyun Park, Hee Juhn Park, Jeong Yeon Seo, WonYoon Chung

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Induction of matrix metalloproteinase (MMP)-9 is particularly important for the invasiveness of breast cancers. We investigated the inhibitory effect of kalopanaxsaponin A (KPS-A) on cell invasion and MMP-9 activation in phorbol 12-myristate 13-acetate (PMA)-treated MCF-7 human breast cancer cells. KPS-A inhibited PMA-induced cell proliferation and invasion. PMA-induced cell invasion was blocked in the presence of a primary antibody of MMP-9, and KPS-A suppressed the increased expression and/or secretion of MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1. Using specific inhibitors, we confirmed that PMA-induced cell invasion and MMP-9 expression is primarily regulated by nuclear factor-kappa B (NF-κB) activation via phosphatidylinositol 3-kinase (PI3K)/Akt and activator protein-1 (AP-1) activation via extracellular signal-regulated kinase (ERK)1/2. KPS-A decreased PMA-induced transcriptional activation of NF-κB and AP-1 and inhibited PMA-induced phosphorylation of ERK1/2 and Akt. Treatment with the protein kinase C (PKC)δ inhibitor rottlerin caused a marked decrease in PMA-induced MMP-9 secretion and cell invasion, as well as ERK/AP-1 activation, and KPS-A reduced PMA-induced membrane localization of PKCδ. Furthermore, oral administration of KPS-A led to a substantial decrease in tumor volume and expression of proliferating cell nuclear antigen, MMP-9, TIMP-1 and PKCδ in mice with MCF-7 breast cancer xenografts in the presence of 17β-estradiol. These results suggest that KPS-A inhibits PMA-induced invasion by reducing MMP-9 activation, mainly via the PI3K/Akt/NF-κB and PKCδ/ERK/ AP-1 pathways in MCF-7 cells and blocks tumor growth and MMP-9-mediated invasiveness in mice with breast carcinoma. Therefore, KPS-A may be a promising anti-invasive agent with the advantage of oral dosing.

Original languageEnglish
Pages (from-to)1225-1233
Number of pages9
JournalCarcinogenesis
Volume30
Issue number7
DOIs
Publication statusPublished - 2009 Jul 15

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Phosphatidylinositol 3-Kinase
Matrix Metalloproteinase 9
Protein Kinase C
Acetates
Breast Neoplasms
Transcription Factor AP-1
Tissue Inhibitor of Metalloproteinase-1
NF-kappa B
Extracellular Signal-Regulated MAP Kinases
Nuclear Matrix
kalopanax saponin A
phorbol-12-myristate
Matrix Metalloproteinase Inhibitors
Mitogen-Activated Protein Kinase 3
Protein C Inhibitor
Mitogen-Activated Protein Kinase 1
MCF-7 Cells
Proliferating Cell Nuclear Antigen
Protein Kinase Inhibitors
Tumor Burden

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Park, Sun Kyu ; Hwang, Young Sun ; Park, Kwang Kyun ; Park, Hee Juhn ; Seo, Jeong Yeon ; Chung, WonYoon. / Kalopanaxsaponin A inhibits PMA-induced invasion by reducing matrix metalloproteinase-9 via PI3K/Akt- and PKCδ-mediated signaling in MCF-7 human breast cancer cells. In: Carcinogenesis. 2009 ; Vol. 30, No. 7. pp. 1225-1233.
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abstract = "Induction of matrix metalloproteinase (MMP)-9 is particularly important for the invasiveness of breast cancers. We investigated the inhibitory effect of kalopanaxsaponin A (KPS-A) on cell invasion and MMP-9 activation in phorbol 12-myristate 13-acetate (PMA)-treated MCF-7 human breast cancer cells. KPS-A inhibited PMA-induced cell proliferation and invasion. PMA-induced cell invasion was blocked in the presence of a primary antibody of MMP-9, and KPS-A suppressed the increased expression and/or secretion of MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1. Using specific inhibitors, we confirmed that PMA-induced cell invasion and MMP-9 expression is primarily regulated by nuclear factor-kappa B (NF-κB) activation via phosphatidylinositol 3-kinase (PI3K)/Akt and activator protein-1 (AP-1) activation via extracellular signal-regulated kinase (ERK)1/2. KPS-A decreased PMA-induced transcriptional activation of NF-κB and AP-1 and inhibited PMA-induced phosphorylation of ERK1/2 and Akt. Treatment with the protein kinase C (PKC)δ inhibitor rottlerin caused a marked decrease in PMA-induced MMP-9 secretion and cell invasion, as well as ERK/AP-1 activation, and KPS-A reduced PMA-induced membrane localization of PKCδ. Furthermore, oral administration of KPS-A led to a substantial decrease in tumor volume and expression of proliferating cell nuclear antigen, MMP-9, TIMP-1 and PKCδ in mice with MCF-7 breast cancer xenografts in the presence of 17β-estradiol. These results suggest that KPS-A inhibits PMA-induced invasion by reducing MMP-9 activation, mainly via the PI3K/Akt/NF-κB and PKCδ/ERK/ AP-1 pathways in MCF-7 cells and blocks tumor growth and MMP-9-mediated invasiveness in mice with breast carcinoma. Therefore, KPS-A may be a promising anti-invasive agent with the advantage of oral dosing.",
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Kalopanaxsaponin A inhibits PMA-induced invasion by reducing matrix metalloproteinase-9 via PI3K/Akt- and PKCδ-mediated signaling in MCF-7 human breast cancer cells. / Park, Sun Kyu; Hwang, Young Sun; Park, Kwang Kyun; Park, Hee Juhn; Seo, Jeong Yeon; Chung, WonYoon.

In: Carcinogenesis, Vol. 30, No. 7, 15.07.2009, p. 1225-1233.

Research output: Contribution to journalArticle

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T1 - Kalopanaxsaponin A inhibits PMA-induced invasion by reducing matrix metalloproteinase-9 via PI3K/Akt- and PKCδ-mediated signaling in MCF-7 human breast cancer cells

AU - Park, Sun Kyu

AU - Hwang, Young Sun

AU - Park, Kwang Kyun

AU - Park, Hee Juhn

AU - Seo, Jeong Yeon

AU - Chung, WonYoon

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AB - Induction of matrix metalloproteinase (MMP)-9 is particularly important for the invasiveness of breast cancers. We investigated the inhibitory effect of kalopanaxsaponin A (KPS-A) on cell invasion and MMP-9 activation in phorbol 12-myristate 13-acetate (PMA)-treated MCF-7 human breast cancer cells. KPS-A inhibited PMA-induced cell proliferation and invasion. PMA-induced cell invasion was blocked in the presence of a primary antibody of MMP-9, and KPS-A suppressed the increased expression and/or secretion of MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1. Using specific inhibitors, we confirmed that PMA-induced cell invasion and MMP-9 expression is primarily regulated by nuclear factor-kappa B (NF-κB) activation via phosphatidylinositol 3-kinase (PI3K)/Akt and activator protein-1 (AP-1) activation via extracellular signal-regulated kinase (ERK)1/2. KPS-A decreased PMA-induced transcriptional activation of NF-κB and AP-1 and inhibited PMA-induced phosphorylation of ERK1/2 and Akt. Treatment with the protein kinase C (PKC)δ inhibitor rottlerin caused a marked decrease in PMA-induced MMP-9 secretion and cell invasion, as well as ERK/AP-1 activation, and KPS-A reduced PMA-induced membrane localization of PKCδ. Furthermore, oral administration of KPS-A led to a substantial decrease in tumor volume and expression of proliferating cell nuclear antigen, MMP-9, TIMP-1 and PKCδ in mice with MCF-7 breast cancer xenografts in the presence of 17β-estradiol. These results suggest that KPS-A inhibits PMA-induced invasion by reducing MMP-9 activation, mainly via the PI3K/Akt/NF-κB and PKCδ/ERK/ AP-1 pathways in MCF-7 cells and blocks tumor growth and MMP-9-mediated invasiveness in mice with breast carcinoma. Therefore, KPS-A may be a promising anti-invasive agent with the advantage of oral dosing.

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