Monensin Inhibits Canonical Wnt Signaling in Human Colorectal Cancer Cells and Suppresses Tumor Growth in Multiple Intestinal Neoplasia Mice
Monensin Inhibits Canonical Wnt Signaling in Human Colorectal Cancer Cells and Suppresses Tumor Growth in Multiple Intestinal Neoplasia Mice
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DOI：
10.1158/1535-7163.mct-13-0625
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发表时间：
2014-04-01
影响因子：
5.7
通讯作者：
Korinek, Vladimir
中科院分区：
文献类型：
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作者：
Tumova, Lucie;Pombinho, Antonio R.;Korinek, Vladimir
Wnt信号通路在胚胎发育期间和维持成体组织的稳态是必需的。然而，该途径的异常激活涉及许多人类疾病，包括胃肠道癌、乳腺癌、肝癌、黑色素瘤和血液恶性肿瘤。在这项研究中，我们确定莫能菌素，聚醚离子载体抗生素，作为一种有效的抑制剂Wnt信号。莫能菌素对Wnt/β-连环蛋白信号级联的抑制作用在用Wnt配体、糖原合成酶激酶-3抑制剂刺激的哺乳动物细胞中以及在用β-连环蛋白表达构建体转染的细胞中观察到。此外，莫能菌素抑制Wnt依赖的尾鳍再生在斑马鱼和Wnt或β-连环蛋白诱导的非洲爪蟾胚胎的第二身体轴的形成。在Wnt 3a激活的HEK 293细胞中，莫能菌素阻断Wnt辅助受体低密度脂蛋白受体相关蛋白6的磷酸化，并促进其降解。在显示Wnt信号失调的人结直肠癌细胞中，莫能菌素降低了β-连环蛋白的细胞内水平。这种减少减弱了Wnt信号转导靶基因如cyclin D1和SP 5的表达，并降低了细胞增殖率。在多发性肠肿瘤（Min）小鼠中，每日给予莫能菌素可抑制肠肿瘤的进展，对正常粘膜无任何毒性迹象。我们的数据表明，莫能菌素作为一个前瞻性的抗癌药物治疗肿瘤与失调的Wnt信号。Mol Cancer Ther; 13（4）; 812-22. (C)2014年AACR。
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.