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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.

Authors
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
Source
Proc Natl Acad Sci U.S.A. 2010 Feb; 107(5):1918-1923
NIOSHTIC No.
20045170
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.
Keywords
Peptides; Tumors; Cell-function; Cell-biology; Cellular-function; Cancer; Pancreatic-islets-neoplasms; Proteins; Drugs; Pharmacology; Metabolism; Pathology; Membrane-dysfunction; Author Keywords: HDM-2 binding; membranolysis; three-dimensional structure; transfection
Contact
Matthew R. Pincus, Department of Pathology and Laboratory Medicine, New York Harbor VA Medical Center, 800 Poly Place, Brooklyn, NY 11209
CODEN
PNASA6
Publication Date
20100201
Document Type
Journal Article
Email Address
matthew.pincus2@med.va.gov
Funding Type
Grant
Fiscal Year
2010
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-007590
Issue of Publication
5
ISSN
0027-8424
Priority Area
Research Tools and Approaches: Cancer Research Methods
Source Name
Proceedings of the National Academy of Sciences of the United States of America
State
NY
Performing Organization
Columbia University Health Sciences
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