Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells

Prodigiosin, a natural red pigment produced by numerous bacterial species, has exhibited promising anticancer activity; however, the molecular mechanisms of action of prodigiosin on malignant cells remain unclear. Aberrant activation of the Wnt/beta-catenin signaling cascade is associated with numerous human cancers. In this study, we identified prodigiosin as a potent inhibitor of the Wnt/beta-catenin pathway. Prodigiosin blocked Wnt/beta-catenin signaling by targeting multiple sites of this pathway, including the low-density lipoprotein-receptor-related protein ( LRP) 6, Dishevelled ( DVL), and glycogen synthase kinase-3 beta ( GSK3 beta). In breast cancer MDA-MB-231 and MDA-MB-468 cells, nanomolar concentrations of prodigiosin decreased phosphorylation of LRP6, DVL2, and GSK3 beta and suppressed beta-catenin-stimulated Wnt target gene expression, including expression of cyclin D1. In MDA-MB-231 breast cancer xenografts andMMTV-Wnt1 transgenic mice, administration of prodigiosin slowed tumor progression and reduced the expression of phosphorylated LRP6, phosphorylated and unphosphorylated DVL2, Ser9 phosphorylated GSK3 beta, active beta-catenin, and cyclin D1. Through its ability to inhibit Wnt/a-catenin signaling and reduce cyclin D1 levels, prodigiosin could have therapeutic activity in advanced breast cancers.