期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：46
页码：13150-13155
DOI：10.1073/pnas.1616336113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe Wnt pathway is implicated in multiple cancers, but to date no pharmacologically acceptable Wnt inhibitors have been introduced into the clinic. Analogs of the natural product prodigiosin are in early leukemia trials, but their mechanisms of action have not been established. We report that prodigiosin and its analog obatoclax block Wnt signaling at nanomolar concentrations by preventing the phosphorylation of Dishevelled. Cyclin D is an established target of Wnt signaling, and elevated cyclin D levels are characteristic of advanced breast cancer. In a Wnt-driven murine transgenic model of breast cancer, prodigiosin potently diminished cyclin D levels and blocked the growth of tumors. These results provide a rationale for the introduction of prodigiosin analogs into clinical trials of advanced breast cancer. 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 and MMTV-Wnt1 transgenic mice, administration of prodigiosin slowed tumor progression and reduced the expression of phosphorylated LRP6, phosphorylated and unphosphorylated DVL2, Ser9 phosphorylated GSK3{beta
关键词：prodigiosin ; Wnt/beta-catenin signaling ; breast cancer ; LRP6 ; Dishevelled (DVL)
