Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637.
Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX 77843.
Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):E7469-E7478. doi: 10.1073/pnas.1621048114. Epub 2017 Aug 21.
Deregulated Wnt signaling and altered lipid metabolism have been linked to obesity, diabetes, and various cancers, highlighting the importance of identifying inhibitors that can modulate Wnt signaling and aberrant lipid metabolism. We have established a model with hyperactivated Wnt signaling caused by partial loss of axin, a key component of the Wnt cascade. The mutant larvae are transparent and have severe adipocyte defects caused by up-regulation of β-catenin transcriptional activities. We demonstrate pharmacologic mitigation of these phenotypes in mutants by identifying bortezomib and additional peptide boronic acids. We show that the suppressive effect of peptide boronic acids on hyperactive Wnt signaling is dependent on α-catenin; the rescue effect is completely abolished with the depletion of α-catenin in adipocytes. These results indicate that rather than targeting the canonical Wnt signaling pathway directly, pharmacologic modulation of β-catenin activity through α-catenin is a potentially attractive approach to attenuating Wnt signaling in vivo.
Wnt 信号的失调和脂质代谢的改变与肥胖、糖尿病和各种癌症有关，这凸显了鉴定能够调节 Wnt 信号和异常脂质代谢的抑制剂的重要性。我们建立了一个模型，其中 Wnt 信号通路的关键成分轴蛋白（axin）部分缺失导致 Wnt 信号的过度激活。这些 突变体幼虫是透明的，由于β-catenin 转录活性的上调，脂肪细胞严重缺陷。我们通过鉴定硼替佐米和其他肽硼酸来证明在 突变体中这些表型的药物缓解。我们表明，肽硼酸对过度活跃的 Wnt 信号的抑制作用依赖于连接蛋白α-catenin；用连接蛋白α-catenin 在脂肪细胞中的耗竭完全消除了挽救作用。这些结果表明，通过连接蛋白α-catenin 对 β-catenin 活性进行药物调节可能是一种有吸引力的方法，而不是直接针对经典的 Wnt 信号通路，从而在体内减弱 Wnt 信号。
