首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells
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Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells

机译:沙利霉素可抑制Wnt信号传导并选择性诱导慢性淋巴细胞白血病细胞凋亡

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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/ p-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 fibronec-tin, 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.
机译:盐霉素,一种抗生素钾离子载体,最近已被报道可以作为选择性的乳腺癌干细胞抑制剂,但是其抗癌作用的生化基础尚不清楚。 Wnt / p-catenin信号转导通路在干细胞发育中起着核心作用,其异常激活可能导致癌症。在这项研究中,我们确定了盐霉素是Wnt信号级联的有效抑制剂。在Wnt转染的HEK293细胞中,沙利霉素可阻断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。尼古丁是另一种具有抗癌干细胞活性的钾离子载体,具有类似的作用。在原本没有操纵的慢性淋巴细胞性白血病中,具有组成性的Wnt激活的纳摩尔浓度的沙利霉素会下调Wnt目标基因(如LEF1,cyclin D1和纤维蛋白)的表达,从而降低LRP6的水平,并限制细胞存活。正常人外周血淋巴细胞抵抗沙利霉素的毒性。这些结果表明,由盐霉素和相关药物诱导的离子变化通过干扰LPR6磷酸化抑制了近端Wnt信号传导,从而损害了依赖Wnt信号在质膜的细胞的存活。

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