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
Externally publishedYes

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Peptides
Membranes
Neoplasms
Cell Membrane
PNC-27
Transfection
Plasmids
Cell Line

ASJC Scopus subject areas

  • General

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

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 5, 02.02.2010, p. 1918-1923.

Research output: Contribution to journalArticle

Sarafraz-Yazdi, E, Bowne, WB, Adler, V, Sookraj, KA, Wu, V, Shteyler, V, Patel, H, Oxbury, W, Brandt-Rauf, P, Zenilman, ME, Michl, J & Pincus, MR 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, vol. 107, no. 5, pp. 1918-1923. https://doi.org/10.1073/pnas.0909364107
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. / Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 5. pp. 1918-1923.
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