Open AccessAscofuranone suppresses PMA-mediated matrix metalloproteinase-9 gene activation through the Ras/Raf/MEK/ERK- and Ap1-dependent mechanisms
Author(s) -
Hyun-Ji Cho,
Jeong Han Kang,
JongYoung Kwak,
Tae-Sung Lee,
In-Seon Lee,
Nam Gyu Park,
Hiroo Nakajima,
Junji Magae,
YoungChae Chang
Publication year - 2006
Publication title -
carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.688
H-Index - 204
eISSN - 1460-2180
pISSN - 0143-3334
DOI - 10.1093/carcin/bgl217
Subject(s) - mapk/erk pathway , ap 1 transcription factor , microbiology and biotechnology , activator (genetics) , protein kinase a , p38 mitogen activated protein kinases , biology , kinase , signal transduction , protein kinase c , cancer research , matrix metalloproteinase , mek inhibitor , chemistry , transcription factor , gene , biochemistry
The expression of matrix metalloproteinase-9 (MMP-9) has been implicated in the invasion and metastasis of cancer cells. Here, we found that an antitumor antibiotic, ascofuranone, inhibits invasion and MMP-9 induction induced by phorbol myristate acetate (PMA) in human cell lines. Ascofuranone also inhibits the protein expression and transcription of MMP-9 induced by tumor necrosis factor-alpha. The inhibition of MMP-9 induction was observed in human cancer cell lines as well as primary rat mesangial cells. Furthermore, as evidenced by MMP-9 promoter and electrophoretic mobility shift assays, ascofuranone specifically inhibited MMP-9 gene expression by blocking PMA-stimulated activation of activator protein-1 (AP-1). In addition, ascofuranone suppressed PMA-induced phosphorylation of Ras, Raf, MEK and extracellular signal-regulated kinase (ERK), upstream factors involved in AP-1activation, whereas the phosphorylation of p38 and JNK/mitogen-activated protein kinase was not affected by ascofuranone, suggesting that the primary target of ascofuranone for suppression of the AP-1 induction is present in upstream of ERK signaling pathway. These results suggest that the suppression of MMP-9 expression, at least in part, contributes to the antitumor activity of ascofuranone.