Cranberry flavonols inhibit matrix metalloproteinase activity in human prostate cancer cells

Abstract

This study examined the effects of a flavonol‐enriched fraction (FL) from cranberry (V. macrocarpon) on MMP activity in DU145 cells. FL was characterized to contain quercetin and myricetin derivatives. MMP‐2/‐9 activity (assessed by zymography) was inhibited by FL. FL (50 ug/mL) decreased cellular viability by 15 % post 6 hours of treatment. The effect of FL treatment on protein modulators of MMPs was evaluated. Treatment of DU145 cells with 50 ug/mL FL for 6 hours resulted in increased expression of TIMP‐2, decreased expression of TIMP‐1 with no change in either EMMPRIN or RECK. The effect of FL on cell signaling proteins was evaluated. FL treatment decreased the expression of p‐ERK, p‐p38 and increased p38 with no change in ERK 1/2 protein levels. JNK‐1, p‐JNK‐2 and pJNK‐1 increased in response to FL treatment., and JNK‐2 was unchanged. AKT protein levels were unchanged following FL treatment while p‐AKT levels decreased. PI3K p85 levels decreased and PI3K p110 levels increased. There was no change in cytoplasmic p65 expression in response to FL whereas nuclear p65 protein levels increased. FL treatment of DU145 cells resulted in decreased c‐fos protein levels and increased c‐jun protein levels. No change in IκBα occurred in response to FL however FL increased the expression of p‐IκBα protein levels. These results suggest that cranberry FL has the ability to inhibit the expression of MMP‐2/‐9 activity in DU145 cells at a concentration which is not substantially cytotoxic to these cells suggesting that FL inhibits MMPs in a targeted manner. The FL‐mediated effects involve a number of cell signaling pathways.[N.C.I.C.‐Canadian Cancer Society, P.E.I. Health Research Program, The Cranberry Institute (Wisconsin Cranberry Board) funded]