Carcinogenesis Advance Access originally published online on May 6, 2009
Carcinogenesis 2009 30(7):1225-1233; doi:10.1093/carcin/bgp111
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Kalopanaxsaponin A inhibits PMA-induced invasion by reducing matrix metalloproteinase-9 via PI3K/Akt- and PKC
-mediated signaling in MCF-7 human breast cancer cells
1 Department of Applied Life Science, The Graduate School, Yonsei University
2 Department of Oral Biology, Brain Korea 21 project
3 Oral Cancer Research Institute, Yonsei University College of Dentistry, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752, Korea
4 Departments of Botanical Resources, Sangji University, Wonju 220-702, Korea
* To whom correspondence should be addressed. Tel: +82 2 2228 3057; Fax: +82 2 364 7113; Email: wychung{at}yuhs.ac
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-
B) 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-B and AP-1 and inhibited PMA-induced phosphorylation of ERK1/2 and Akt. Treatment with the protein kinase C (PKC)
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 PKC. 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 PKC 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-B and PKC/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.
Abbreviations: AP-1, activator protein-1; DMEM, Dulbecco's modified Eagle's medium; ERK, extracellular signal-regulated kinase; FBS, fetal bovine serum; JNK, c-jun N-terminal kinase; KPS-A, kalopanaxsaponin A; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NF-B, nuclear factor-kappa B; PBS, phosphate-buffered saline; PCNA, proliferating cell nuclear antigen; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate; TIMP, tissue inhibitor of metalloproteinase
These authors contributed equally to this work. Received November 19, 2008; revised April 4, 2009; accepted May 2, 2009.