Characterization of the MUC1-C Cytoplasmic Domain as a Cancer Target

• Published in: PloS one Vol. 10; no. 8; p. e0135156
• Main Authors: Raina, Deepak, Agarwal, Praveen, Lee, James, Bharti, Ajit, McKnight, C James, Sharma, Pankaj, Kharbanda, Surender, Kufe, Donald
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.08.2015; Public Library of Science (PLoS)
• Subjects: Acids; Amino Acid Motifs; Amino Acid Sequence; Amino acids; Breast cancer; Cancer; Carcinoma; Cell Line, Tumor; Cell surface; Cell survival; Conserved sequence; Disulfide bonds; HEK293 Cells; Humans; Kinases; Lung cancer; Lung diseases; Medical prognosis; Medical schools; Molecular Sequence Data; Mucin; Mucin-1 - chemistry; Mucin-1 - metabolism; Neural networks; Peptides; Protein Binding; Protein Multimerization; Protein Structure, Tertiary; Protein Transport; Proteins; Receptors; United States > US; India
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0135156

Mucin 1 (MUC1) is a heterodimeric protein that is aberrantly expressed in diverse human carcinomas and certain hematologic malignancies. The oncogenic MUC1 transmembrane C-terminal subunit (MUC1-C) functions in part by transducing growth and survival signals from cell surface receptors. However, little is known about the structure of the MUC1-C cytoplasmic domain as a potential drug target. Using methods for structural predictions, our results indicate that a highly conserved CQCRRK sequence, which is adjacent to the cell membrane, forms a small pocket that exposes the two cysteine residues for forming disulfide bonds. By contrast, the remainder of the MUC1-C cytoplasmic domain has no apparent structure, consistent with an intrinsically disordered protein. Our studies thus focused on targeting the MUC1 CQCRRK region. The results show that L- and D-amino acid CQCRRK-containing peptides bind directly to the CQC motif. We further show that the D-amino acid peptide, designated GO-203, blocks homodimerization of the MUC1-C cytoplasmic domain in vitro and in transfected cells. Moreover, GO-203 binds directly to endogenous MUC1-C in breast and lung cancer cells. Colocalization studies further demonstrate that GO-203 predominantly binds to MUC1-C at the cell membrane. These findings support the further development of agents that target the MUC1-C cytoplasmic domain CQC motif and thereby MUC1-C function in cancer cells.