Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 5; pp. 1918 - 1923
• Main Authors: Sarafraz-Yazdi, Ehsan, Bowne, Wilbur B, Adler, Victor, Sookraj, Kelley A, Wu, Vernon, Shteyler, Vadim, Patel, Hunaiz, Oxbury, William, Brandt-Rauf, Paul, Zenilman, Michael E, Michl, Josef, Pincus, Matthew R
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.02.2010; National Acad Sciences
• Subjects: Amino Acid Sequence; Antibodies; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; B lymphocytes; Base Sequence; Binding Sites; Biological Sciences; Cancer; Cell Death - drug effects; Cell growth; Cell Line; Cell Line, Tumor; Cell lines; Cell Membrane - metabolism; Cell membranes; Cells; Crystallography, X-Ray; Female; Fluorescence; Fluorescent Dyes; Humans; Male; Membranes; Microscopy, Confocal; Models, Molecular; Molecular Sequence Data; Molecular structure; Nuclear Magnetic Resonance, Biomolecular; P branes; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Peptides; Plasmids; Plasmids - genetics; Protein Conformation; Proteins; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Stem cells; Transfection; Tumor Suppressor Protein p53 - chemistry; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Protein p53 - pharmacology; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0909364107

The anticancer peptide PNC-27, which contains an HDM-2-binding domain corresponding to residues 12-26 of p53 and a transmembrane-penetrating domain, has been found to kill cancer cells (but not normal cells) by inducing membranolysis. We find that our previously determined 3D structure of the p53 residues of PNC-27 is directly superimposable on the structure for the same residues bound to HDM-2, suggesting that the peptide may target HDM-2 in the membranes of cancer cells. We now find significant levels of HDM-2 in the membranes of a variety of cancer cells but not in the membranes of several untransformed cell lines. In colocalization experiments, we find that PNC-27 binds to cell membrane-bound HDM-2. We further transfected a plasmid expressing full-length HDM-2 with a membrane-localization signal into untransformed MCF-10-2A cells not susceptible to PNC-27 and found that these cells expressing full-length HDM-2 on their cell surface became susceptible to PNC-27. We conclude that PNC-27 targets HDM-2 in the membranes of cancer cells, allowing it to induce membranolysis of these cells selectively.