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Interaction of two antitumor peptides with membrane lipids – Influence of phosphatidylserine and cholesterol on specificity for melanoma cells

R-DIM-P-LF11-322 and DIM-LF11-318, derived from the cationic human host defense peptide lactoferricin show antitumor activity against human melanoma. While R-DIM-P-LF11-322 interacts specifically with cancer cells, the non-specific DIM-LF11-318 exhibits as well activity against non-neoplastic cells....

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Autores principales: Wodlej, Christina, Riedl, Sabrina, Rinner, Beate, Leber, Regina, Drechsler, Carina, Voelker, Dennis R., Choi, Jae-Yeon, Lohner, Karl, Zweytick, Dagmar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347193/
https://www.ncbi.nlm.nih.gov/pubmed/30682171
http://dx.doi.org/10.1371/journal.pone.0211187
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author Wodlej, Christina
Riedl, Sabrina
Rinner, Beate
Leber, Regina
Drechsler, Carina
Voelker, Dennis R.
Choi, Jae-Yeon
Lohner, Karl
Zweytick, Dagmar
author_facet Wodlej, Christina
Riedl, Sabrina
Rinner, Beate
Leber, Regina
Drechsler, Carina
Voelker, Dennis R.
Choi, Jae-Yeon
Lohner, Karl
Zweytick, Dagmar
author_sort Wodlej, Christina
collection PubMed
description R-DIM-P-LF11-322 and DIM-LF11-318, derived from the cationic human host defense peptide lactoferricin show antitumor activity against human melanoma. While R-DIM-P-LF11-322 interacts specifically with cancer cells, the non-specific DIM-LF11-318 exhibits as well activity against non-neoplastic cells. Recently we have shown that cancer cells expose the negatively charged lipid phosphatidylserine (PS) in the outer leaflet of the plasma membrane, while non-cancer cells just expose zwitterionic or neutral lipids, such as phosphatidylcholine (PC) or cholesterol. Calorimetric and zeta potential studies with R-DIM-P-LF11-322 and cancer-mimetic liposomes composed of PS, PC and cholesterol indicate that the cancer-specific peptide interacts specifically with PS. Cholesterol, however, reduces the effectiveness of the peptide. The non-specific DIM-LF11-318 interacts with PC and PS. Cholesterol does not affect its interaction. The dependence of activity of R-DIM-P-LF11-322 on the presence of exposed PS was also confirmed in vitro upon PS depletion of the outer leaflet of cancer cells by the enzyme PS-decarboxylase. Further corresponding to model studies, cholesterol depleted melanoma plasma membranes showed increased sensitivity to R-DIM-P-LF11-322, whereas activity of DIM-LF11-318 was unaffected. Microscopic studies using giant unilamellar vesicles and melanoma cells revealed strong changes in lateral distribution and domain formation of lipids upon addition of both peptides. Whereas R-DIM-P-LF11-322 enters the cancer cell specifically via PS and reaches an intracellular organelle, the Golgi, inducing mitochondrial swelling and apoptosis, DIM-LF11-318 kills rapidly and non-specifically by lysis of the plasma membrane. In conclusion, the specific interaction of R-DIM-P-LF11-322 with PS and sensitivity to cholesterol seem to modulate its specificity for cancer membranes.
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spelling pubmed-63471932019-02-02 Interaction of two antitumor peptides with membrane lipids – Influence of phosphatidylserine and cholesterol on specificity for melanoma cells Wodlej, Christina Riedl, Sabrina Rinner, Beate Leber, Regina Drechsler, Carina Voelker, Dennis R. Choi, Jae-Yeon Lohner, Karl Zweytick, Dagmar PLoS One Research Article R-DIM-P-LF11-322 and DIM-LF11-318, derived from the cationic human host defense peptide lactoferricin show antitumor activity against human melanoma. While R-DIM-P-LF11-322 interacts specifically with cancer cells, the non-specific DIM-LF11-318 exhibits as well activity against non-neoplastic cells. Recently we have shown that cancer cells expose the negatively charged lipid phosphatidylserine (PS) in the outer leaflet of the plasma membrane, while non-cancer cells just expose zwitterionic or neutral lipids, such as phosphatidylcholine (PC) or cholesterol. Calorimetric and zeta potential studies with R-DIM-P-LF11-322 and cancer-mimetic liposomes composed of PS, PC and cholesterol indicate that the cancer-specific peptide interacts specifically with PS. Cholesterol, however, reduces the effectiveness of the peptide. The non-specific DIM-LF11-318 interacts with PC and PS. Cholesterol does not affect its interaction. The dependence of activity of R-DIM-P-LF11-322 on the presence of exposed PS was also confirmed in vitro upon PS depletion of the outer leaflet of cancer cells by the enzyme PS-decarboxylase. Further corresponding to model studies, cholesterol depleted melanoma plasma membranes showed increased sensitivity to R-DIM-P-LF11-322, whereas activity of DIM-LF11-318 was unaffected. Microscopic studies using giant unilamellar vesicles and melanoma cells revealed strong changes in lateral distribution and domain formation of lipids upon addition of both peptides. Whereas R-DIM-P-LF11-322 enters the cancer cell specifically via PS and reaches an intracellular organelle, the Golgi, inducing mitochondrial swelling and apoptosis, DIM-LF11-318 kills rapidly and non-specifically by lysis of the plasma membrane. In conclusion, the specific interaction of R-DIM-P-LF11-322 with PS and sensitivity to cholesterol seem to modulate its specificity for cancer membranes. Public Library of Science 2019-01-25 /pmc/articles/PMC6347193/ /pubmed/30682171 http://dx.doi.org/10.1371/journal.pone.0211187 Text en © 2019 Wodlej et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Wodlej, Christina
Riedl, Sabrina
Rinner, Beate
Leber, Regina
Drechsler, Carina
Voelker, Dennis R.
Choi, Jae-Yeon
Lohner, Karl
Zweytick, Dagmar
Interaction of two antitumor peptides with membrane lipids – Influence of phosphatidylserine and cholesterol on specificity for melanoma cells
title Interaction of two antitumor peptides with membrane lipids – Influence of phosphatidylserine and cholesterol on specificity for melanoma cells
title_full Interaction of two antitumor peptides with membrane lipids – Influence of phosphatidylserine and cholesterol on specificity for melanoma cells
title_fullStr Interaction of two antitumor peptides with membrane lipids – Influence of phosphatidylserine and cholesterol on specificity for melanoma cells
title_full_unstemmed Interaction of two antitumor peptides with membrane lipids – Influence of phosphatidylserine and cholesterol on specificity for melanoma cells
title_short Interaction of two antitumor peptides with membrane lipids – Influence of phosphatidylserine and cholesterol on specificity for melanoma cells
title_sort interaction of two antitumor peptides with membrane lipids – influence of phosphatidylserine and cholesterol on specificity for melanoma cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347193/
https://www.ncbi.nlm.nih.gov/pubmed/30682171
http://dx.doi.org/10.1371/journal.pone.0211187
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