Journal article
The Anti-Cancer Peptide, PNC-27, Induces Tumor Cell Necrosis of a Poorly Differentiated Non-Solid Tissue Human Leukemia Cell Line that Depends on Expression of HDM-2 in the Plasma Membrane of these Cells
Annals of clinical and laboratory science, v 44(3), pp 241-248
01 Jun 2014
PMID: 25117093
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Goals. We have developed the anti-cancer peptide, PNC-27, which is a membrane-active peptide that binds to the HDM-2 protein expressed in the cancer cell membranes of solid tissue tumor cells and induces transmembrane pore formation in cancer, but not in normal cells, resulting in tumor cell necrosis that is independent of p53 activity in these cells. We now extend our study to non-solid tissue tumor cells, in this case, a primitive, possible stem cell human leukemia cell line (K562) that is also p53-homozygously deleted. Our purpose was twofold: to investigate if these cells likewise express HDM-2 in their plasma membranes and to determine if our anti-cancer peptide induces tumor cell necrosis in these non-solid tissue tumor cells in a manner that depends on the interaction between the peptide and membrane-bound HDM-2. Procedures. The anti-cancer activity and mechanism of PNC-27, which carries a p53 aa12-26-leader sequence connected on its carboxyl terminal end to a trans-membrane-penetrating sequence or membrane residency peptide (MRP), was studied against p53-null K562 leukemia cells. Murine leukocytes were used as a non-cancer cell control. Necrosis was determined by measuring the lactate dehydrogenase (LDH) release and apoptosis was determined by the detection of Caspases 3 and 7. Membrane colocalization of PNC-27 with HDM-2 was analyzed microscopically using fluorescently labeled antibodies against HDM-2 and PNC-27 peptides. Results. We found that K562 cells strongly express HDM-2 protein in their membranes and that PNC-27 co-localizes with this protein in the membranes of these cells. PNC-27, but not the negative control peptide PNC-29, is selectively cytotoxic to K562 cells, inducing nearly 100 percent cell killing with LDH release. In contrast, this peptide had no effect on the lymphocyte control cells. Conclusions. The results suggest that HDM-2 is expressed in the membranes of non-solid tissue tumor cells in addition to the membranes of solid tissue tumor cells. Since K-562 cells appear to be in the stem cell family, the results suggest that early developing tumor cells also express HDM-2 protein in their membranes. Since PNC-27 induces necrosis of K-562 leukemia cells and co-localizes with HDM-2 in the tumor cell membrane as an early event, we conclude that the association of PNC-27 with HDM-2 in the cancer cell membrane results in trans-membrane pore formation which results in cancer cell death, as previously discovered in a number of different solid tissue tumor cells. Since K562 cells lack p53 expression, these effects of PNC-27 on this leukemia cell line occur by a p53-independent pathway.
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Details
- Title
- The Anti-Cancer Peptide, PNC-27, Induces Tumor Cell Necrosis of a Poorly Differentiated Non-Solid Tissue Human Leukemia Cell Line that Depends on Expression of HDM-2 in the Plasma Membrane of these Cells
- Creators
- Katlin Davitt - Drexel Univ, Coll Med, Dept Surg, Philadelphia, PA 19102 USABlake D. Babcock - Drexel Univ, Coll Med, Dept Surg, Philadelphia, PA 19102 USAMaly Fenelus - Suny Downstate Med Ctr, Dept Surg, Brooklyn, NY 11203 USAChi Kong Poon - Suny Downstate Med Ctr, Dept Surg, Brooklyn, NY 11203 USAAbhishek Sarkar - Suny Downstate Med Ctr, Dept Surg, Brooklyn, NY 11203 USAVincent Trivigno - Suny Downstate Med Ctr, Dept Surg, Brooklyn, NY 11203 USAPaul A. Zolkind - Suny Downstate Med Ctr, Dept Surg, Brooklyn, NY 11203 USASheena M. Matthew - Suny Downstate Med Ctr, Dept Surg, Brooklyn, NY 11203 USANatalia Grin'kina - Suny Downstate Med Ctr, Dept Microbiol & Anat & Cell Biol, Div Pharmacol & Physiol, Brooklyn, NY 11203 USAZulfiya Orynbayeva - Drexel UniversityMohammad F. Shaikh - Drexel Univ, Coll Med, Dept Surg, Philadelphia, PA 19102 USAVictor Adler - Drexel Univ, Coll Med, Dept Surg, Philadelphia, PA 19102 USAJosef Michl - Suny Downstate Med Ctr, Dept Pathol, Brooklyn, NY 11203 USAEhsan Sarafraz-Yazdi - Suny Downstate Med Ctr, Dept Pathol, Brooklyn, NY 11203 USAMatthew R. Pincus - Suny Downstate Med Ctr, Dept Pathol, Brooklyn, NY 11203 USAWilbur B. Bowne - Drexel Univ, Coll Med, Dept Surg, Philadelphia, PA 19102 USA
- Publication Details
- Annals of clinical and laboratory science, v 44(3), pp 241-248
- Publisher
- Assoc Clinical Scientists
- Number of pages
- 8
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Surgery
- Web of Science ID
- WOS:000344755600001
- Scopus ID
- 2-s2.0-84906249700
- Other Identifier
- 991019167414004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Medical Laboratory Technology