Abstract
Among plant polyphenols, lemon peels extract (LPE) from the residues of the industrial processing of lemon (Citrus limon) shows anti-proliferative properties in cancer cells and anticholinesterase activity. In this study, we analyze the anti-cancer properties of LPE on migration and invasiveness in MKN-28 and AGS human gastric cancer cell lines either in the absence or presence of the pro-inflammatory cytokine IL-6. We find that the pretreatment with non-cytotoxic concentrations (0.5–1 μg/ml of gallic acid equivalent) of LPE inhibits interleukin-6 (IL-6)-induced cell migration and invasiveness in MKN-28 and AGS cells, as analyzed by wound and matrigel assays. Pretreatment with LPE is able to prevent either IL-6-induced matrix metalloproteinases (MMP)-9/2 activity, as assessed by gel zymography, or mRNA and protein MMP-9/2 expression, as evaluated by qPCR and Western blotting analysis, respectively. These LPE effects are associated with an IL-6-dependent STAT3 signaling pathway in MKN-28 and AGS cells. Furthermore, LPE shows acetylcholinesterase inhibitory activity when assayed by the Ellman method. In conclusion, our results demonstrate that LPE reduces the invasiveness of gastric MKN-28 and AGS cancer cells through the reduction of IL-6-induced MMP-9/2 up-regulation. Therefore, these data suggest that LPE exerts a protective role against the metastatic process in gastric cancer.
Highlights
Gastric cancer (GC) is one of the most common malignant tumors in the world, with relatively high mortality [1]
Our results indicate that lemon peel extract (LPE) is able to inhibit recombinant IL-6-dependent migration and invasiveness associated with the up-regulation of matrix metalloproteinases (MMP)-9 and MMP-2 expression levels in human gastric carcinoma MKN-28 and AGS cell lines
Since IL-6 causes an increase of migration and invasiveness in gastric cancer cells [1,14,15,27,28], we investigated the effect of LPE treatment on recombinant IL-6 (rIL-6)-induced migration and invasive ability by wound healing and matrigel invasion assays, respectively, in MKN-28 and AGS cells
Summary
Gastric cancer (GC) is one of the most common malignant tumors in the world, with relatively high mortality [1]. Due to the high metastatic ability of gastric cancer cells, the GC prognosis is complex to determine. A key step in the complex processes of invasion and migration of cancer cells is caused by the degradation of the extracellular matrix (ECM). MMPs are a family of zinc-dependent endo-peptidases secreted as inactive zymogens by stromal and tumor cells, and the cleavage of the pro-domain peptide yields their active form [4]. Some members of the MMP family, especially MMP-2 and MMP-9, known as gelatinases A and B, are critically involved in tumor invasion, and metastasis and their expression have been associated with poor overall survival in patients with gastric cancer [5,6,7]
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