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

作者：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

来源：Proceedings of the National Academy of Sciences of the United States of America, 2010, 107(5): 1918-1923.

DOI：10.1073/pnas.0909364107

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

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.

• 出版日期2010-2-2