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.
Footnotes
This work was supported by the National Institutes of Health National Cancer Institute [Grants CA097098, CA42808].
D.K. holds equity in Genus Oncology and is a consultant to the company.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.070797.
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ABBREVIATIONS:
- MUC1
- mucin 1
- MUC1-C
- mucin 1 C-terminal subunit
- MUC1-CD
- mucin 1 cytoplasmic domain
- PBS
- phosphate-buffered saline
- HRP
- horseradish peroxidase
- DMSO
- dimethyl sulfoxide
- GFP
- green fluorescent protein
- ERα
- estrogen receptor-α
- MTS
- 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt
- PI3K
- PI3K, phosphatidylinositol 3-kinase
- ICCB
- Institute of Chemistry and Cell Biology.
- Received December 22, 2010.
- Accepted February 23, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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