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.

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.

• Authors: Sun Kyu Park, Young Sun Hwang, Kwang-Kyun Park, Hee-Juhn Park, Jeong Yeon Seo, Won-Yoon Chung
• Journal: Carcinogenesis (Carcinogenesis) Vol. 30 Issue 7 Pg. 1225-33 (Jul 2009) ISSN: 1460-2180 [Electronic] England
• PMID: 19420016 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetophenones
• Antineoplastic Agents, Phytogenic
• Benzopyrans
• NF-kappa B
• Phosphoinositide-3 Kinase Inhibitors
• Saponins
• Transcription Factor AP-1
• kalopanax saponin A
• Oleanolic Acid
• rottlerin
• Proto-Oncogene Proteins c-akt
• Protein Kinase C-delta
• Extracellular Signal-Regulated MAP Kinases
• Matrix Metalloproteinase 9
• Tetradecanoylphorbol Acetate

Topics

• Acetophenones (pharmacology)
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology, therapeutic use)
• Benzopyrans (pharmacology)
• Breast Neoplasms (chemically induced, pathology, prevention & control)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Humans
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred BALB C
• NF-kappa B (antagonists & inhibitors, metabolism)
• Neoplasm Invasiveness
• Neoplasm Transplantation
• Oleanolic Acid (analogs & derivatives, pharmacology, therapeutic use)
• Phosphatidylinositol 3-Kinases (physiology)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase C-delta (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-akt (physiology)
• Saponins (pharmacology, therapeutic use)
• Signal Transduction
• Tetradecanoylphorbol Acetate
• Transcription Factor AP-1 (metabolism)
• Transplantation, Heterologous