Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes
Autor: | Hunaiz Patel, Victor Adler, Ehsan Sarafraz-Yazdi, Vernon Wu, Josef Michl, Matthew R. Pincus, Wilbur B. Bowne, Paul W. Brandt-Rauf, Kelley A. Sookraj, Michael E. Zenilman, Vadim Shteyler, William Oxbury |
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Jazyk: | angličtina |
Rok vydání: | 2010 |
Předmět: |
Male
Models Molecular Protein Conformation Recombinant Fusion Proteins Cell Molecular Sequence Data Peptide Antineoplastic Agents Biology Crystallography X-Ray Transfection Cell Line Cell membrane Cell Line Tumor medicine Humans Amino Acid Sequence Peptide sequence Nuclear Magnetic Resonance Biomolecular Fluorescent Dyes chemistry.chemical_classification Multidisciplinary Binding Sites Microscopy Confocal Base Sequence Cell Death Cell Membrane Proto-Oncogene Proteins c-mdm2 Biological Sciences Peptide Fragments Cell biology Membrane medicine.anatomical_structure chemistry Cell culture Cancer cell Female Tumor Suppressor Protein p53 Plasmids |
Popis: | 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. |
Databáze: | OpenAIRE |
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