Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Mol Pharmacol. 2011 May;79(5):886-93. doi: 10.1124/mol.110.070797. Epub 2011 Feb 23.
Mucin 1 (MUC1) is a heterodimeric protein that is overexpressed in diverse human carcinomas. The oncogenic function of the MUC1 C-terminal subunit (MUC1-C) subunit is dependent on the formation of dimers through its cytoplasmic domain; however, it is not known whether MUC1-C can be targeted with small-molecule inhibitors. In the present work, an assay using the MUC1-C cytoplasmic domain (MUC1-CD) was established to screen small-molecule libraries for compounds that block its dimerization. Using this approach, the flavone apigenin was identified as an inhibitor of MUC1-CD dimerization in vitro and in cells. By contrast, the structurally related flavone baicalein was ineffective in blocking the formation of MUC1-CD dimers. In concert with these results, apigenin, and not baicalein, blocked the localization of MUC1-C to the nucleus. MUC1-C activates MUC1 gene expression in an autoinductive loop, and apigenin, but not baicalein, treatment was associated with down-regulation of MUC1 mRNA levels and MUC1-C protein. The results also demonstrate that apigenin-induced suppression of MUC1-C expression is associated with apoptotic cell death and loss of clonogenic survival. These findings represent the first demonstration that the MUC1-C cytoplasmic domain is a target for the development of small-molecule inhibitors.
黏蛋白 1（MUC1）是一种异二聚体蛋白，在多种人类癌中过表达。MUC1 C 端亚基（MUC1-C）的致癌功能依赖于其胞质域形成二聚体；然而，是否可以用小分子抑制剂来靶向 MUC1-C 尚不清楚。在本工作中，建立了一种使用 MUC1-C 胞质域（MUC1-CD）的测定法，以筛选可阻断其二聚化的小分子文库。使用这种方法，鉴定出类黄酮芹菜素是体外和细胞内 MUC1-CD 二聚化的抑制剂。相比之下，结构相关的类黄酮黄芩素不能有效地阻断 MUC1-CD 二聚体的形成。与这些结果一致，芹菜素而非黄芩素阻断了 MUC1-C 向核的定位。MUC1-C 在自动诱导环中激活 MUC1 基因表达，而芹菜素而非黄芩素处理与 MUC1 mRNA 水平和 MUC1-C 蛋白的下调相关。结果还表明，芹菜素诱导的 MUC1-C 表达抑制与细胞凋亡和集落形成存活丧失有关。这些发现代表了第一个证明 MUC1-C 胞质域是小分子抑制剂开发的靶标的证据。
