Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes.
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.
Sarafraz-Yazdi
Ehsan
E
Cell and Molecular Biology Program, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
Bowne
Wilbur B
WB
Adler
Victor
V
Sookraj
Kelley A
KA
Wu
Vernon
V
Shteyler
Vadim
V
Patel
Hunaiz
H
Oxbury
William
W
Brandt-Rauf
Paul
P
Zenilman
Michael E
ME
Michl
Josef
J
Pincus
Matthew R
MR
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D005260:Female; D005456:Fluorescent Dyes; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2