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

Details

• Personal Author:
  Adler V ; Bowne WB ; Brandt-Rauf P ; Michl J ; Oxbury W ; Patel H ; Pincus MR ; Sarafraz-Yazdi E ; Shteyler V ; Sookraj KA ; Wu V ; Zenilman ME
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Energy Metabolism Neoplasms Occupational Health Pathology Safety
• Keywords:
  Author Keywords: HDM-2 Binding Cancer Cell-biology Cell-function Cellular-function Drugs Membrane-dysfunction Membranolysis Metabolism Pancreatic-islets-neoplasms Peptides Pharmacology Proteins Three-dimensional Structure Transfection Tumors

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• ISSN:
  0027-8424
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  New York ; OSHA Region 2
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  107
• Issue:
  5
• NIOSHTIC Number:
  nn:20045170
• Citation:
  Proc Natl Acad Sci U.S.A. 2010 Feb; 107(5):1918-1923
• Contact Point Address:
  Matthew R. Pincus, Department of Pathology and Laboratory Medicine, New York Harbor VA Medical Center, 800 Poly Place, Brooklyn, NY 11209
• Email:
  matthew.pincus2@med.va.gov
• Federal Fiscal Year:
  2010
• NORA Priority Area:
  Research Tools and Approaches: Cancer Research Methods
• Performing Organization:
  Columbia University Health Sciences
• Peer Reviewed:
  True
• Start Date:
  20020601
• Source Full Name:
  Proceedings of the National Academy of Sciences of the United States of America
• End Date:
  20110630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:e94d165809427e331246d00232ab42b65f615ec5ff223c147a1e0e93c68f9f274d1be0379ab932d61d0bad9d0f0494a0f1b72d1883af8755c7ce9f92f55e444b
• Download URL:
  https://stacks.cdc.gov/view/cdc/200686/cdc_200686_DS1.pdf
• File Type:
  [PDF - 604.33 KB ]