Lemon Peel Polyphenol Extract Reduces Interleukin-6-Induced Cell Migration, Invasiveness, and Matrix Metalloproteinase-9/2 Expression in Human Gastric Adenocarcinoma MKN-28 and AGS Cell Lines

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 ?g/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.