title: Monensin inhibits canonical Wnt signaling in human colorectal cancer cells and suppresses tumor growth in multiple intestinal neoplasia mice.
abstract: The Wnt signaling pathway is required during embryonic development and for the maintenance of homeostasis in adult tissues. However, aberrant activation of the pathway is implicated in a number of human disorders, including cancer of the gastrointestinal tract, breast, liver, melanoma, and hematologic malignancies. In this study, we identified monensin, a polyether ionophore antibiotic, as a potent inhibitor of Wnt signaling. The inhibitory effect of monensin on the Wnt/β-catenin signaling cascade was observed in mammalian cells stimulated with Wnt ligands, glycogen synthase kinase-3 inhibitors, and in cells transfected with β-catenin expression constructs. Furthermore, monensin suppressed the Wnt-dependent tail fin regeneration in zebrafish and Wnt- or β-catenin-induced formation of secondary body axis in Xenopus embryos. In Wnt3a-activated HEK293 cells, monensin blocked the phoshorylation of Wnt coreceptor low-density lipoprotein receptor related protein 6 and promoted its degradation. In human colorectal carcinoma cells displaying deregulated Wnt signaling, monensin reduced the intracellular levels of β-catenin. The reduction attenuated the expression of Wnt signaling target genes such as cyclin D1 and SP5 and decreased the cell proliferation rate. In multiple intestinal neoplasia (Min) mice, daily administration of monensin suppressed progression of the intestinal tumors without any sign of toxicity on normal mucosa. Our data suggest monensin as a prospective anticancer drug for therapy of neoplasia with deregulated Wnt signaling.
authors.affiliation: Authors' Affiliations: Department of Cell and Developmental Biology, CZ-OPENSCREEN, Institute of Molecular Genetics AS CR; Department of Organic Chemistry, Faculty of Science, Charles University in Prague, Prague; and Central European Institute of Technology, Masaryk University, Brno, Czech Republic; and Zoologisches Institut II, Universität Karlsruhe, Karlsruhe, Germany.
authors.forename: Lucie
authors.initials: L
authors.lastname: Tumova
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Pombinho
authors.forename: Martina
authors.initials: M
authors.lastname: Vojtechova
authors.forename: Jitka
authors.initials: J
authors.lastname: Stancikova
authors.forename: Dietmar
authors.initials: D
authors.lastname: Gradl
authors.forename: Michaela
authors.initials: M
authors.lastname: Krausova
authors.forename: Eva
authors.initials: E
authors.lastname: Sloncova
authors.forename: Monika
authors.initials: M
authors.lastname: Horazna
authors.forename: Vitezslav
authors.initials: V
authors.lastname: Kriz
authors.forename: Olga
authors.initials: O
authors.lastname: Machonova
authors.forename: Jindrich
authors.initials: J
authors.lastname: Jindrich
authors.forename: Zbynek
authors.initials: Z
authors.lastname: Zdrahal
authors.forename: Petr
authors.initials: P
authors.lastname: Bartunek
authors.forename: Vladimir
authors.initials: V
authors.lastname: Korinek
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D051379:Mice; D008985:Monensin / Q000494:pharmacology* / Q000627:therapeutic use; D009374:Neoplasms, Experimental; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D014981:Xenopus; D015027:Zebrafish; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051176:beta Catenin; D008985:Monensin