Glycitein inhibits glioma cell invasion through down-regulation of MMP-3 and MMP-9 gene expression.
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that play a pivotal role in invasion and angiogenesis of malignant glioma cells. Therefore, the inhibition of MMPs has been suggested to be a promising therapeutic strategy for brain tumors. In the present study, we found that glycitein, a bacterial metabolite of the isoflavone glycitin, inhibits the expression of MMP-3 and MMP-9 at promoter, mRNA, and protein levels in PMA-stimulated U87MG human astroglioma cells. In addition, gelatin zymography showed that glycitein inhibited the PMA-induced MMP-9 secretion in U87MG cells. A subsequent Matrigel invasion assay revealed that glycitein suppresses the in vitro invasiveness of glioma cells, which may be at least partly due to the glycitein-mediated inhibition of MMP-3 and MMP-9. In support of this, treatment of MMP-3- or MMP-9-specific inhibitor significantly suppressed PMA-induced invasion of glioma cells. Further mechanistic studies revealed that glycitein inhibits the DNA binding and transcriptional activities of NF-kappaB and AP-1, which are important transcription factors for MMP-3 or MMP-9 gene expression. Furthermore, glycitein suppresses PMA-induced phosphorylation of three types of MAP kinases, which are upstream signaling molecules in MMP gene expressions and NF-kappaB and AP-1 activities in glioma cells. Therefore, the inhibition of MMP-3 and MMP-9 expression by glycitein may have therapeutic potential for controlling invasiveness of malignant gliomas.
Lee
Eun-Jung
EJ
Department of Molecular Medicine, Ewha Womans University Medical School, Seoul, Republic of Korea.
Kim
So-Young
SY
Hyun
Jin-Won
JW
Min
Sung-Won
SW
Kim
Dong-Hyun
DH
Kim
Hee-Sun
HS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009457:Neuroglia / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D007529:Isoflavones; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D004247:DNA; C086566:glycitein; D020928:Mitogen-Activated Protein Kinases; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9