Mucin 1 C-terminal subunit oncoprotein is a target for small-molecule inhibitors

Mol Pharmacol. 2011 May;79(5):886-93. doi: 10.1124/mol.110.070797. Epub 2011 Feb 23.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Apigenin / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dimerization
  • Down-Regulation / drug effects
  • Humans
  • Molecular Sequence Data
  • Mucin-1 / chemistry
  • Mucin-1 / drug effects*
  • Mucin-1 / genetics
  • Oncogene Proteins / antagonists & inhibitors*
  • Oncogene Proteins / chemistry
  • Oncogene Proteins / genetics
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Mucin-1
  • Oncogene Proteins
  • RNA, Messenger
  • Apigenin