Nobiletin, a Citrus Flavonoid, Down-Regulates Matrix Metalloproteinase-7 (matrilysin) Expression in HT-29 Human Colorectal Cancer Cells

Abstract

Overexpression of matrix metalloproteinases (MMPs) is associated with cancer metastasis. We assessed mRNA expression of MMPs in six human colorectal cancer cell lines and found a considerable level of MMP-7 expression in HT-29 cells. Next, we searched for natural and synthetic compounds that cause a reduction in the production of proMMP-7 protein, and found that nobiletin (NOB), quercetin, valeryl salicylate, and sulindac sulfone demonstrated marked inhibition. Importantly, NOB attenuated proMMP-7 protein and its mRNA expression both concentration-and time-dependently via a reduction of activator protein-1 (AP-1) DNA binding activity, suggesting it as a promising agent for suppression of cancer cell invasion and metastasis through MMP-7 gene repression.

Modifying Effects of Dietary Factors on (−)-Epigallocatechin-3-gallate-induced Pro-matrix Metalloproteinase-7 Production in HT-29 Human Colorectal Cancer Cells

“…AP-1 is an important transcription factor that contributes to MMP-7 expression. 42) EGCG alone enhanced the AP-1 DNA binding activity, as also shown in previous studies, 9,43) and BITC, GA and NAC suppressed that activity in the present experiments (Fig. 3).…”

Correlation between Flavonoid Content and the NO Production Inhibitory Activity of Peel Extracts from Various Citrus Fruits

“…41) Citrus nobiletin also inhibits azoxymethane-induced large bowel carcinogenesis in rats and down-regulates matrix metalloproteinase-7 expression in HT-29 human colorectal cancer cells. 42,43) In conclusion, the flavonoid contents and NO production inhibitory effects of the peel extracts investigated in this study were unique to each citrus plant. Among the seven flavonoids analyzed, the nobiletin content and NO production inhibitory effect of each citrus fruit peel were highly correlated.…”

Antimetastatic effect of nobiletin through the down-regulation of CXC chemokine receptor type 4 and matrix metallopeptidase-9

“…Nobiletin helps to lower cholesterol levels (Whitman et al, 2005) and some studies indicate that it may improve impaired memory loss (Onozuka et al, 2008) and treat acne (Sato et al, 2007). Nobiletin has been shown to exhibit antitumor activities as indicated by the attenuation of pro-MMP-7 protein and its mRNA expression in HT-29 cells (Kawabata et al, 2005), down-regulation of leptin levels in mice with azoxymethane-and dextran sulfate sodium-induced colon carcinogenesis (Miyamoto et al, 2008), and the suppression of invasion and migration in human gastric adenocarcinoma AGS cells (Lee et al, 2011). Since CXCR4 plays an important role in tumor growth and metastasis, we postulated that nobiletin may modulate the expression of CXCR4 and MMP-9 and suppress tumor cell invasion.…”