Inhibition of MMP-9 transcription and suppression of tumor metastasis by pyrrole-imidazole polyamide.
Matrix metalloproteinase (MMP)-9, the 92-kDa type IV collagenase, contributes to tumor invasion and metastases, and strategies to down-regulate its expression could ultimately be of clinical utility. A pyrrole-imidazole (PI) polyamide that targets the activator protein-1 (AP-1)-binding site of the MMP-9 promoter was designed and synthesized as a gene-silencing agent for tumor metastases. The synthesized product showed selective DNA binding ability. The MMP-9 PI polyamide significantly inhibited MMP-9's mRNA expression, protein level, and enzymatic activity in human breast adenocarcinoma cells (MDA-MB-231). Furthermore, the MMP-9 PI polyamide inhibited migration and invasion by in vitro wound-healing and matrigel-invasion assay. The FITC-labeled PI polyamide was localized in nuclei in 45 min of incubation with an MDA-MB-231 cell and remained in the nuclei for up to 96 h after incubation in vitro. It was also quickly localized in the mouse cellular nuclei of many tissues, including liver, kidney, and spleen, after intravenous injection without using any drug-delivery system. Moreover, the polyamide treatment significantly decreased metastasis in a mouse model of liver metastasis. Our results suggest that this PI polyamide, which targets the MMP-9 gene promoter, can be a novel MMP-9 down-regulating molecule for antimetastasis.
Wang
Xiaofei
X
Life Science, Advanced Research Institute for the Sciences and Humanities, Nihon University, Tokyo, Japan.
Nagase
Hiroki
H
Watanabe
Takayoshi
T
Nobusue
Hiroyuki
H
Suzuki
Tsukasa
T
Asami
Yukihiro
Y
Shinojima
Yui
Y
Kawashima
Hiroyuki
H
Takagi
Keiko
K
Mishra
Rajeev
R
Igarashi
Jun
J
Kimura
Makoto
M
Takayama
Tadatoshi
T
Fukuda
Noboru
N
Sugiyama
Hiroshi
H
D000818:Animals; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009757:Nylons / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011758:Pyrroles / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*
D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D009757:Nylons; D011758:Pyrroles; D020780:Matrix Metalloproteinase 9