Ascofuranone suppresses PMA-mediated matrix metalloproteinase-9 gene activation through the Ras/Raf/MEK/ERK- and Ap1-dependent mechanisms.
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.
Cho
Hyun-Ji
HJ
Department of Pathology, Catholic University of Daegu School of Medicine, 3056-6, Daemyung-4-Dong, Nam-gu, Daegu 705-718, Korea.
Kang
Jeong Han
JH
Kwak
Jong-Young
JY
Lee
Tae-Sung
TS
Lee
In-Seon
IS
Park
Nam Gyu
NG
Nakajima
Hiroo
H
Magae
Junji
J
Chang
Young-Chae
YC
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D011905:Genes, ras; D006801:Humans; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051381:Rats; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D048490:raf Kinases / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D012717:Sesquiterpenes; D018808:Transcription Factor AP-1; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9; C006640:ascofuranone; D013755:Tetradecanoylphorbol Acetate