Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes
Edited by Harold A. Scheraga, Cornell University, Ithaca, NY, and approved November 17, 2009 (received for review August 28, 2009)
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.
Acknowledgments.
This work was supported in part by a grant from Innomab Inc. (to M.R.P. and J.M) and by National Institutes of Health Grant CA42500, a Veterans Administration Merit Grant (to M.R.P.), a Lustgarten Foundation for Pancreatic Cancer Research Grant (to M.R.P. and J.M.), and a Veterans Administration Grant and an American College of Surgeons Faculty Research Fellowship Award (to W.B.B.).
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Cover image: Pictured are an adult male and an infant chacma baboon. Peter Henzi et al. report that alpha male chacma baboons, who control reproductive access to females, concede mating opportunities to subordinate males. The presence of subordinate fathers, who protect their own and other infants, compensates for the high probability that alpha males will be absent when their own offspring are vulnerable to attack. See the article by Henzi et al. on pages 2130–2135. Photograph courtesy of S.P. Henzi.
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Published online: January 11, 2010
Published in issue: February 2, 2010
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Acknowledgments
This work was supported in part by a grant from Innomab Inc. (to M.R.P. and J.M) and by National Institutes of Health Grant CA42500, a Veterans Administration Merit Grant (to M.R.P.), a Lustgarten Foundation for Pancreatic Cancer Research Grant (to M.R.P. and J.M.), and a Veterans Administration Grant and an American College of Surgeons Faculty Research Fellowship Award (to W.B.B.).
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This article is a PNAS Direct Submission.
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The authors declare no conflict of interest.
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