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

Ehsan Sarafraz-Yazdi, Wilbur B. Bowne, Victor Adler, Kelley A. Sookraj, Vernon Wu, Vadim Shteyler, Hunaiz Patel, William Oxbury, Paul Brandt-Rauf, Michael E. Zenilman, Josef Michl, Matthew R. Pincus

Research output: Contribution to journalArticle

Abstract

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. HDM-2 binding membranolysis three-dimensional structure transfection.

Original languageEnglish (US)
Pages (from-to)1918-1923
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number5
DOIs
StatePublished - Feb 2 2010

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    Sarafraz-Yazdi, E., Bowne, W. B., Adler, V., Sookraj, K. A., Wu, V., Shteyler, V., Patel, H., Oxbury, W., Brandt-Rauf, P., Zenilman, M. E., Michl, J., & Pincus, M. R. (2010). Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes. Proceedings of the National Academy of Sciences of the United States of America, 107(5), 1918-1923. https://doi.org/10.1073/pnas.0909364107