Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells
Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells
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DOI：
10.1073/pnas.1110431108
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发表时间：
2011-08-09
影响因子：
11.1
通讯作者：
Carson, Dennis A.
中科院分区：
文献类型：
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作者：
Lu, Desheng;Choi, Michael Y.;Carson, Dennis A.
盐霉素是一种抗生素钾离子载体，最近被报道作为一种选择性乳腺癌干细胞抑制剂，但其抗癌作用的生化基础尚不清楚。Wnt/β-catenin信号转导通路在干细胞发育中起核心作用，其异常激活可导致癌症。在这项研究中，我们发现盐霉素是Wnt信号级联的有效抑制剂。在转导Wnt的HEK293细胞中，盐霉素阻断Wnt共受体脂蛋白受体相关蛋白6(LRP6)的磷酸化，并诱导其降解。另一种具有抗癌干细胞活性的钾离子载体尼日利亚霉素也发挥了类似的作用。在其他未经处理的具有Wnt结构性激活的慢性淋巴细胞白血病细胞中，盐霉素的纳摩尔浓度下调了Wnt靶基因的表达，如LEF1、细胞周期蛋白D1和纤维连接蛋白，抑制了LRP6水平，限制了细胞存活。正常人外周血淋巴细胞能抵抗盐霉素毒性。这些结果表明，盐霉素和相关药物引起的离子变化通过干扰LPR6的磷酸化抑制了近端的Wnt信号，从而损害了依赖质膜上Wnt信号的细胞的生存。
Salinomycin, an antibiotic potassium ionophore, has been reported recently to act as a selective breast cancer stem cell inhibitor, but the biochemical basis for its anticancer effects is not clear. The Wnt/beta-catenin signal transduction pathway plays a central role in stem cell development, and its aberrant activation can cause cancer. In this study, we identified salinomycin as a potent inhibitor of the Wnt signaling cascade. In Wnt-transfected HEK293 cells, salinomycin blocked the phosphorylation of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and induced its degradation. Nigericin, another potassium ionophore with activity against cancer stem cells, exerted similar effects. In otherwise unmanipulated chronic lymphocytic leukemia cells with constitutive Wnt activation nanomolar concentrations of salinomycin down-regulated the expression of Wnt target genes such as LEF1, cyclin D1, and fibronectin, depressed LRP6 levels, and limited cell survival. Normal human peripheral blood lymphocytes resisted salinomycin toxicity. These results indicate that ionic changes induced by salinomycin and related drugs inhibit proximal Wnt signaling by interfering with LPR6 phosphorylation, and thus impair the survival of cells that depend on Wnt signaling at the plasma membrane.