title: Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells.
abstract: 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/β-catenin signaling cascade is associated with numerous human cancers. In this study, we identified prodigiosin as a potent inhibitor of the Wnt/β-catenin pathway. Prodigiosin blocked Wnt/β-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-3β (GSK3β). In breast cancer MDA-MB-231 and MDA-MB-468 cells, nanomolar concentrations of prodigiosin decreased phosphorylation of LRP6, DVL2, and GSK3β and suppressed β-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 GSK3β, active β-catenin, and cyclin D1. Through its ability to inhibit Wnt/β-catenin signaling and reduce cyclin D1 levels, prodigiosin could have therapeutic activity in advanced breast cancers.
authors: Cancer Research Center, Department of Pharmacology, School of Medicine, Shenzhen University, Shenzhen 518060, China.
authors: Zhongyuan
authors: Z
authors: Wang
authors: Cancer Research Center, Department of Pharmacology, School of Medicine, Shenzhen University, Shenzhen 518060, China.|Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China.
authors: Bo
authors: B
authors: Li
authors: Cancer Research Center, Department of Pharmacology, School of Medicine, Shenzhen University, Shenzhen 518060, China.
authors: Liang
authors: L
authors: Zhou
authors: Cancer Research Center, Department of Pharmacology, School of Medicine, Shenzhen University, Shenzhen 518060, China.
authors: Shubin
authors: S
authors: Yu
authors: Cancer Research Center, Department of Pharmacology, School of Medicine, Shenzhen University, Shenzhen 518060, China.|Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China.
authors: Zijie
authors: Z
authors: Su
authors: Cancer Research Center, Department of Pharmacology, School of Medicine, Shenzhen University, Shenzhen 518060, China.|Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China.
authors: Jiaxing
authors: J
authors: Song
authors: Cancer Research Center, Department of Pharmacology, School of Medicine, Shenzhen University, Shenzhen 518060, China.
authors: Qi
authors: Q
authors: Sun
authors: Cancer Research Center, Department of Pharmacology, School of Medicine, Shenzhen University, Shenzhen 518060, China.
authors: Ou
authors: O
authors: Sha
authors: Cancer Research Center, Department of Pharmacology, School of Medicine, Shenzhen University, Shenzhen 518060, China.
authors: Xiaomei
authors: X
authors: Wang
authors: Cancer Research Center, Department of Pharmacology, School of Medicine, Shenzhen University, Shenzhen 518060, China.
authors: Wenqi
authors: W
authors: Jiang
authors: Department of Cellular and Molecular Medicine, Stem Cell Program, University of California, San Diego, La Jolla, CA 92093.
authors: Karl
authors: K
authors: Willert
authors: Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China.
authors: Lei
authors: L
authors: Wei
authors: Cancer Research Center, Department of Pharmacology, School of Medicine, Shenzhen University, Shenzhen 518060, China; delu@szu.edu.cn dcarson@ucsd.edu.|Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors: Dennis A
authors: DA
authors: Carson
authors: Cancer Research Center, Department of Pharmacology, School of Medicine, Shenzhen University, Shenzhen 518060, China; delu@szu.edu.cn dcarson@ucsd.edu.
authors: Desheng
authors: D
authors: Lu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D000072261:Dishevelled Proteins / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D011353:Prodigiosin / Q000494:pharmacology* / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D000072261:Dishevelled Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D011353:Prodigiosin
keywords: Dishevelled (DVL); LRP6; Wnt/beta-catenin signaling; breast cancer; prodigiosin