Monensin Inhibits Canonical Wnt Signaling in Human Colorectal Cancer Cells and Suppresses Tumor Growth in Multiple Intestinal Neoplasia Mice

0435312 - ÚMG 2015 RIV US eng J - Článek v odborném periodiku
Tůmová, Lucie - Pombinho, António R. - Vojtěchová, Martina - Stančíková, Jitka - Gradl, D. - Krausová, Michaela - Šloncová, Eva - Horázná, Monika - Kříž, Vítězslav - Machoňová, Olga - Jindřich, Jindřich - Zdráhal, Z. - Bartůněk, Petr - Kořínek, Vladimír
Monensin Inhibits Canonical Wnt Signaling in Human Colorectal Cancer Cells and Suppresses Tumor Growth in Multiple Intestinal Neoplasia Mice.
Molecular Cancer Therapeutics. Roč. 13, č. 4 (2014), s. 812-822. ISSN 1535-7163. E-ISSN 1538-8514
Grant CEP: GA ČR GAP305/12/2347; GA MPO FR-TI4/802; GA MŠMT LM2011022; GA MŠMT LO1220
Institucionální podpora: RVO:68378050
Klíčová slova: bate-catenin * throughput screen * small molecule inhibitors
Kód oboru RIV: EB - Genetika a molekulární biologie
Impakt faktor: 5.683, rok: 2014

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/beta-catenin signaling cascade was observed in mammalian cells stimulated with Wnt ligands, glycogen synthase kinase-3 inhibitors, and in cells transfected with beta-catenin expression constructs. Furthermore, monensin suppressed the Wnt-dependent tail fin regeneration in zebrafish and Wnt- or beta-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 beta-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. Mol Cancer Ther; 13(4); 812-22. (C) 2014 AACR.
Trvalý link: http://hdl.handle.net/11104/0239216