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 varietyof 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.