Gene interactions and pathways from curated databases and text-mining
Carcinogenesis 2009, PMID: 19420016

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.

Park, Sun Kyu; Hwang, Young Sun; Park, Kwang-Kyun; Park, Hee-Juhn; Seo, Jeong Yeon; Chung, Won-Yoon

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.

Diseases/Pathways annotated by Medline MESH: Breast Neoplasms, Neoplasm Invasiveness
Document information provided by NCBI PubMed

Text Mining Data

MMP-9 → nuclear factor-kappa B (NF-kappaB): " 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 "

ERK1/2 ⊣ AP-1: " KPS-A decreased PMA induced transcriptional activation of NF-kappaB and AP-1 and inhibited PMA induced phosphorylation of ERK1/2 and Akt "

ERK1/2 ⊣ NF-kappaB: " KPS-A decreased PMA induced transcriptional activation of NF-kappaB and AP-1 and inhibited PMA induced phosphorylation of ERK1/2 and Akt "

AP-1 ⊣ Akt: " KPS-A decreased PMA induced transcriptional activation of NF-kappaB and AP-1 and inhibited PMA induced phosphorylation of ERK1/2 and Akt "

Akt ⊣ NF-kappaB: " KPS-A decreased PMA induced transcriptional activation of NF-kappaB and AP-1 and inhibited PMA induced phosphorylation of ERK1/2 and Akt "

Manually curated Databases

No curated data.