Dietary anthocyanidin delphinidin modulates β-catenin signaling pathway in human prostate cancer PC-3 cells

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Prostate cancer (PCa) is the most commonly diagnosed cancer in men within the Western world and the third leading cause of cancer related deaths. Because of unsatisfactory treatment options for PCa there is a need to develop novel preventive approaches for this malignancy. One such strategy is through chemoprevention by the use of non toxic dietary substances and botanical products. Delphinidin, the most abundant and major anthocyanidin present in pigmented fruits and vegetables, possesses strong anti-oxidant and anti-inflammatory properties. Inhibition of Wnt/β-catenin signaling pathway is an attractive target for new chemopreventive and chemotherapeutic approaches. The Wnt signaling pathway and its key component β-catenin play critical roles in embryonic development as well as in human diseases, including various malignancies. Since deregulation of β-catenin signaling pathway contributes to PCa progression, we examined the effect of delphinidin on β-catenin signaling pathway in human prostate cancer PC3 cells. We found that delphinidin (30-180µM; 72 h) treatment resulted in a dose-dependent growth inhibition of cells as assessed by an MTT assay. Delphinidin treatment to cells also resulted in increased phosphorylation of β-catenin at serine and threonine residues and decreased the levels of cytoplasmic β-catenin. Furthermore, treatment of cells to delphinidin inhibited nuclear translocation of β-catenin and suppressed the expression of cyclin D, c-myc, axin-2 and T cell factor-1 (TCF-1) which are downstream target genes of β-catenin. Employing electrophoretic mobility shift assay, we found that treatment of cells with delphinidin decreased the TCF DNA binding activity. We further investigated the effect of delphinidin on β-catenin destruction complex by analyzing the expression of APC, GSK3β and axin. Delphinidin treatment of cells was found to result in the induction of phosphorylation of GSK3β, and protein expression of APC and axin. Moreover, delphinidin treatment resulted in modulation of E-cadherin, Frzb/secreted Frizzled-related protein-3 (FRP3), low density lipoprotein receptor-related protein 6 (LRP6), Dickkopf (Dkk-1) and Dishevelled (Dvl2) proteins. Our results indicate that cell growth inhibition of cells by delphinidin is mediated, at least in part, by modulating β-catenin signaling pathway. We suggest that delphinidin could be a potent inhibitor of Wnt/β-catenin signaling in human prostate cancer cells and suggests its potential use as a cancer therapeutic agent against PCa.