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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-E; Bowne-WB; Adler-V; Sookraj-KA; Wu-V; Shteyler-V; Patel-H; Oxbury-W; Brandt-Rauf-P; Zenilman-ME; Michl-J; Pincus-MR
Proc Natl Acad Sci U.S.A. 2010 Feb; 107(5):1918-1923
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.
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
Matthew R. Pincus, Department of Pathology and Laboratory Medicine, New York Harbor VA Medical Center, 800 Poly Place, Brooklyn, NY 11209
Issue of Publication
Research Tools and Approaches: Cancer Research Methods
Proceedings of the National Academy of Sciences of the United States of America
Columbia University Health Sciences
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