Article

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

Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Korea.
Carcinogenesis (Impact Factor: 5.64). 06/2009; 30(7):1225-33. DOI: 10.1093/carcin/bgp111
Source: PubMed

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-kappaB) 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-kappaB and AP-1 and inhibited PMA-induced phosphorylation of ERK1/2 and Akt. Treatment with the protein kinase C (PKC)delta 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 PKCdelta. 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 PKCdelta in mice with MCF-7 breast cancer xenografts in the presence of 17beta-estradiol. These results suggest that KPS-A inhibits PMA-induced invasion by reducing MMP-9 activation, mainly via the PI3K/Akt/NF-kappaB and PKCdelta/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.

0 Bookmarks
 · 
186 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gallic acid and anthocyanins are abundant plant food bioactives present in many fruits and vegetables, being especially important in the composition of berries. Gallic acid has been shown to possess cytotoxic properties in several cancer cell lines and to inhibit carcinogenesis in animal models. However, its mechanism of action is not yet fully understood. The aim of this study was to elucidate whether the observed inhibitory activity of gallic acid against gelatinases corresponds to its cytotoxic activity in HT1080 cells and to determine if anthocyanins could exhibit a similar behavior. Gallic acid and delphinidin-3-glucoside have shown selective cytotoxicity towards HT1080 cells. Further analysis by a migration and invasion assay showed anti-invasive activities of gallic acid, delphinidin and pelargonidin-3-glucosides. Zymographic analysis demonstrated the inhibitory activity of gallic acid at the level of secreted and activated gelatinases. Moreover, gallic acid inhibited MMP-2 and MMP-9 proteolytic activity with very similar potency. NMR and molecular modelling experiments confirmed the interaction of gallic acid with MMP-2, and suggested that it takes place within the catalytic center. In this work we give some new experimental data supporting the role of these compounds in the inhibition of metalloproteases as the mechanism for their cytotoxic activity against fibrosarcoma.
    Food & function. 01/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the effects of dihydromyricetin (DHM) on the migration and invasion of human hepatic cancer cells.
    World journal of gastroenterology : WJG. 08/2014; 20(29):10082-93.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gambogic acid (GA), a xanthone derived from the resin of the Garcinia hanburyi, has been demonstrated possessing anti-metastatic activity in vitro and in vivo. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a membrane-anchored glycoprotein negatively regulating matrix metalloproteinases (MMPs), plays an important role in tumor invasion and metastasis. The present study investigates the regulatory effect of GA on RECK expression and the role of RECK in GA-induced anti-invasion in A549 human lung cancer cells. Our results showed that GA dose-dependently inhibited cell invasion and suppressed A549 experimental lung metastasis in vivo, which was attributed to RECK up-regulation at both protein and mRNA levels. With small interference RNA (siRNA) blocking RECK expression, we found inhibition of RECK decreased the GA-induced inhibition of MMP-2/9, which was in consistent with the attenuated anti-invasive effect of GA. Further study indicated that GA effectively suppressed Histone deacetylase (HDAC) 1/specificity protein (Sp) 1 binding and Sp1 phosphorylation associating with Extracellular signal-regulated kinases (ERK) signaling blocking, leading to RECK up-regulation. Taken together, these data demonstrate that RECK contributes to GA's anti-invasive activity and provide new evidence for GA being served as a therapeutic candidate for cancer metastasis. © 2014 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 02/2014; · 4.27 Impact Factor

Full-text

View
54 Downloads
Available from
May 31, 2014