Carboxylated chitooligosaccharides (CCOS) inhibit MMP-9 expression in human fibrosarcoma cells via down-regulation of AP-1.
Matrix metalloproteinases (MMPs) play a fundamental role in invasion and metastasis of tumor and, recent advances in medicinal chemistry have approached designing of MMP inhibitors with desired structural properties, selectivity and bioavailability. In the present study, novel low-molecular-weight carboxylated chitooligosaccharides (CCOS) were evaluated for their MMP-9 inhibitory effect on human fibrosarcoma cell line (HT1080). In zymography experiments, a clear dose-dependent inhibition on MMP-9 mediated gelatinolytic activities were observed in HT1080 cells following treatment with CCOS. Further, transfection studies carried out with MMP-9 and AP-1 reporter constructs suggested that the observed reduction in MMP-9 expression was due to down-regulation of MMP-9 transcription that mediated via inhibition of AP-1. Moreover, expression of c-Fos protein levels in cytoplasm and nucleus confirmed that CCOS could inhibit AP-1 expression but not its translocation. However, in the presence of CCOS, NF-kappaB and TIMP-1 expression levels remained constant. More importantly, inhibition of MMP-9 expression clearly led to inhibit tumor invasiveness that was studied with reconstituted basement membrane matrix proteins coated synthetic membranes. Taken together, this study discusses MMP-9 inhibition potential of CCOS and their involvement to demote degradation and cellular invasion of extracellular matrix (ECM) and basement membrane. Thus, control of MMP-9 expression by CCOS has considerable significance for the regulation of tumor progression.
Rajapakse
Niranjan
N
Department of Chemistry, Pukyong National University, Busan, South Korea.
Kim
Moon-Moo
MM
Mendis
Eresha
E
Huang
Ronghua
R
Kim
Se-Kwon
SK
D015153:Blotting, Western; D002236:Carbohydrate Conformation; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D005354:Fibrosarcoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D009844:Oligosaccharides / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D061965:Matrix Metalloproteinase Inhibitors; D009844:Oligosaccharides; D011480:Protease Inhibitors; D018808:Transcription Factor AP-1; D020780:Matrix Metalloproteinase 9