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.
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.
Park
Sun Kyu
SK
Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Korea.
Hwang
Young Sun
YS
Park
Kwang-Kyun
KK
Park
Hee-Juhn
HJ
Seo
Jeong Yeon
JY
Chung
Won-Yoon
WY
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D001578:Benzopyrans / Q000494:pharmacology; D001943:Breast Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D012503:Saponins / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014183:Transplantation, Heterologous
D000098:Acetophenones; D000972:Antineoplastic Agents, Phytogenic; D001578:Benzopyrans; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9; D016328:NF-kappa B; D009828:Oleanolic Acid; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051745:Protein Kinase C-delta; D051057:Proto-Oncogene Proteins c-akt; D012503:Saponins; D013755:Tetradecanoylphorbol Acetate; D018808:Transcription Factor AP-1; C460644:kalopanax saponin A; C085746:rottlerin