Identification and Characterization of a Small-Molecule Inhibitor of Wnt Signaling in Glioblastoma Cells
Identification and Characterization of a Small-Molecule Inhibitor of Wnt Signaling in Glioblastoma Cells
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DOI：
10.1158/1535-7163.mct-12-1176-t
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发表时间：
2013-07-01
影响因子：
5.7
通讯作者：
Salerno, Massimiliano
中科院分区：
文献类型：
--
作者：
De Robertis, Alessandra;Valensin, Silvia;Salerno, Massimiliano
多形性胶质母细胞瘤（GBM）是最常见和预后不利的脑肿瘤形式。这些肿瘤的侵袭性和高度侵袭性表型使其成为解剖学上最具破坏性的人类癌症之一，中位生存期不到1年。尽管癌症中典型的Wnt通路激活历来与涉及该通路关键组分（APC、β -连环蛋白或轴蛋白）的突变存在相关，但越来越多的研究表明，GBM中Wnt信号的升高是由涉及该疾病不同阶段的几种替代机制引发的。因此，抑制Wnt信号可能是GBM治疗的一种治疗相关方法。在选择了对Wnt抑制有反应的GBM细胞模型后，我们开始开发一种筛选方法，以鉴定能够调节GBM细胞中典型Wnt信号传导和相关增殖反应的化合物。在这里，我们发现小分子SEN461抑制GBM细胞中典型的Wnt信号通路，在体外和体内的分子和表型水平上都有相关的作用。这些包括sen461诱导的轴蛋白稳定，β -连环蛋白磷酸化/降解增加，以及体外抑制人GBM细胞系和患者来源的原发肿瘤细胞的非锚定生长。此外，体内给药SEN461可以拮抗爪蟾胚胎中的Wnt信号，并降低GBM异种移植模型中的肿瘤生长。这些数据首次证明，小分子介导的Wnt信号抑制可能是GBM治疗的潜在途径。(c) 2013年aacr。
Glioblastoma multiforme (GBM) is the most common and prognostically unfavorable form of brain tumor. The aggressive and highly invasive phenotype of these tumors makes them among the most anatomically damaging human cancers with a median survival of less than 1 year. Although canonical Wnt pathway activation in cancers has been historically linked to the presence of mutations involving key components of the pathway (APC, beta-catenin, or Axin proteins), an increasing number of studies suggest that elevated Wnt signaling in GBM is initiated by several alternative mechanisms that are involved in different steps of the disease. Therefore, inhibition of Wnt signaling may represent a therapeutically relevant approach for GBM treatment. After the selection of a GBM cell model responsive to Wnt inhibition, we set out to develop a screening approach for the identification of compounds capable of modulating canonical Wnt signaling and associated proliferative responses in GBM cells. Here, we show that the small molecule SEN461 inhibits the canonical Wnt signaling pathway in GBM cells, with relevant effects at both molecular and phenotypic levels in vitro and in vivo. These include SEN461-induced Axin stabilization, increased beta-catenin phosphorylation/degradation, and inhibition of anchorage-independent growth of human GBM cell lines and patient-derived primary tumor cells in vitro. Moreover, in vivo administration of SEN461 antagonized Wnt signaling in Xenopus embryos and reduced tumor growth in a GBM xenograft model. These data represent the first demonstration that small-molecule-mediated inhibition of Wnt signaling may be a potential approach for GBM therapeutics. (C) 2013 AACR.