Section for Cellular and Genetic Therapy, Institute of Microbiology, Oslo University Hospital, and Norwegian Center for Stem Cell Research, Forskningsparken, Oslo, Norway.
Cancer Res. 2011 Jan 1;71(1):197-205. doi: 10.1158/0008-5472.CAN-10-1282.
Canonical Wnt signaling is deregulated in several types of human cancer where it plays a central role in tumor cell growth and progression. Here we report the identification of 2 new small molecules that specifically inhibit canonical Wnt pathway at the level of the destruction complex. Specificity was verified in various cellular reporter systems, a Xenopus double-axis formation assay and a gene expression profile analysis. In human colorectal cancer (CRC) cells, the new compounds JW67 and JW74 rapidly reduced active β-catenin with a subsequent downregulation of Wnt target genes, including AXIN2, SP5, and NKD1. Notably, AXIN2 protein levels were strongly increased after compound exposure. Long-term treatment with JW74 inhibited the growth of tumor cells in both a mouse xenograft model of CRC and in Apc(Min) mice (multiple intestinal neoplasia, Min). Our findings rationalize further preclinical and clinical evaluation of these new compounds as novel modalities for cancer treatment.
经典 Wnt 信号通路在多种人类癌症中失调，在肿瘤细胞生长和进展中发挥核心作用。在这里，我们报告了两种新的小分子的鉴定，它们可以特异性地抑制破坏复合物水平上的经典 Wnt 通路。在各种细胞报告系统、非洲爪蟾双轴形成测定和基因表达谱分析中验证了特异性。在人结直肠癌细胞 (CRC) 中，新型化合物 JW67 和 JW74 可迅速减少活性 β-连环蛋白，随后下调 Wnt 靶基因，包括 AXIN2、SP5 和 NKD1。值得注意的是，化合物暴露后 AXIN2 蛋白水平显着增加。长期用 JW74 治疗可抑制 CRC 小鼠异种移植模型和 Apc(Min)小鼠（多发性肠肿瘤，Min）中的肿瘤细胞生长。我们的研究结果为这些新型化合物作为癌症治疗的新方法进行进一步的临床前和临床评估提供了依据。
