Wnt Inhibitor Screen Reveals Iron Dependence of β-Catenin Signaling in Cancers
Wnt Inhibitor Screen Reveals Iron Dependence of β-Catenin Signaling in Cancers
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DOI：
10.1158/0008-5472.can-11-2745
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发表时间：
2011-12-15
期刊：
影响因子：
11.2
通讯作者：
Attisano, Liliana
中科院分区：
文献类型：
--
作者：
Song, Siyuan;Christova, Tania;Attisano, Liliana
来自Wnt通路的过度信号传导与许多人类癌症相关。使用设计用于检测Wnt/β-连环蛋白信号传导抑制剂的高通量筛选，我们鉴定了一系列酰基腙，其作用于β-连环蛋白破坏复合物的下游以通过β-连环蛋白的去稳定化来抑制Wnt诱导的和癌症相关的组成性Wnt信号传导。我们发现这些酰基腙在体外和完整细胞中结合铁，并且需要螯合活性来废除Wnt信号传导并阻断具有组成性Wnt信号传导的结直肠癌细胞系的生长。此外，我们发现多种铁螯合剂，去铁胺，地拉罗司和环吡酮胺类似地阻断Wnt信号传导和细胞生长。此外，在服用环吡酮胺的AML患者中，我们观察到白血病细胞中Wnt靶基因AXIN 2的表达降低。因此，这类新的酰基腙将是进一步开发作为化疗剂的主要候选物。总之，我们的研究结果揭示了Wnt信号传导中对铁的关键需求，并且它们表明铁螯合作用是抑制人类Wnt信号传导的有效机制。Cancer Res; 71（24）; 7628-39.（C）2011年《非洲标准化评论》。
Excessive signaling from the Wnt pathway is associated with numerous human cancers. Using a high throughput screen designed to detect inhibitors of Wnt/beta-catenin signaling, we identified a series of acyl hydrazones that act downstream of the beta-catenin destruction complex to inhibit both Wnt-induced and cancer-associated constitutive Wnt signaling via destabilization of beta-catenin. We found that these acyl hydrazones bind iron in vitro and in intact cells and that chelating activity is required to abrogate Wnt signaling and block the growth of colorectal cancer cell lines with constitutive Wnt signaling. In addition, we found that multiple iron chelators, desferrioxamine, deferasirox, and ciclopirox olamine similarly blocked Wnt signaling and cell growth. Moreover, in patients with AML administered ciclopirox olamine, we observed decreased expression of the Wnt target gene AXIN2 in leukemic cells. The novel class of acyl hydrazones would thus be prime candidates for further development as chemotherapeutic agents. Taken together, our results reveal a critical requirement for iron in Wnt signaling and they show that iron chelation serves as an effective mechanism to inhibit Wnt signaling in humans. Cancer Res; 71(24); 7628-39. (C)2011 AACR.