TY - JOUR T1 - MUC1-C ONCOPROTEIN IS A TARGET FOR SMALL MOLECULE INHIBITORS JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.110.070797 SP - mol.110.070797 AU - John Zhou AU - Hasan Rajabi AU - Donald W. Kufe Y1 - 2011/02/23 UR - http://molpharm.aspetjournals.org/content/early/2011/02/23/mol.110.070797.abstract N2 - MUC1 is a heterodimeric protein that is overexpressed in diverse human carcinomas. The oncogenic function of the MUC1-C subunit is dependent on the formation of dimers through its cytoplasmic domain; however, it is not known if 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 formation of MUC1-CD dimers. In concert with these results, apigenin, and not baicalein, blocked localization of MUC1-C to the nucleus. MUC1-C activates MUC1 gene expression in an auto-inductive loop, and apigenin, but not baicalein, treatment was associated with downregulation 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. ER -