Lemon peel polyphenols affect invasiveness of human gastric AGS and MKN28 cells by inhibition of IL-6 induced matrix metalloproteinase-9/2

Polyphenols are very abundant in food of mediterranean diet and, in the last years, they are subjects of increasing scientific interest for their potential health benefits against development of cancer, cardiovascular diseases, diabetes, osteoporosis and neu- rodegenerative diseases. In this study, we investigated the effects of lemon peel extracts (LPE) on human gastric adenocarcinoma MKN28 and AGS cell lines. First, we evaluated the effect of LPE on the invasive ability of AGS and MKN28 cells stimulated with IL-6, a pro-inflammatory factor. Migration and Matrigel invasion assays demonstrated that the pre-treatment with LPE (0.5 or 1 lg/mL gallic acid equivalent) provoked an inhibition of cell invasiveness induced by IL-6. In addition, LPE preincubation prevented the increase of Matrix Metalloproteinases (MMP)-9/2 mRNA and protein levels, whose expression is up-regulated by IL-6. Our results indicated that the pre-treatment with LPE was able to reduce MMP-9/2 expression at both protein and enzyme activity levels in the conditioned media of IL-6 stimulated MKN- 28 and AGS cells. Finally, we have analyzed the effect of LPE on STAT3 levels, a transcriptional factor that becomes activated after phosphorylation by IL-6. In conclusion, our results suggest 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, our data confirm the protective effects that LPE could exert against the metastatic process in gastric cancer.