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The plant defensin NaD1 induces tumor cell death via a non-apoptotic, membranolytic process

Cationic anti-microbial peptides (CAPs) have an important role in host innate defense against pathogens such as bacteria and fungi. Many CAPs including defensins also exhibit selective cytotoxic activity towards mammalian cells via both apoptotic and non-apoptotic processes, and are being investigat...

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Autores principales: Baxter, Amy A, Poon, Ivan KH, Hulett, Mark D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253418/
https://www.ncbi.nlm.nih.gov/pubmed/28179997
http://dx.doi.org/10.1038/cddiscovery.2016.102
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author Baxter, Amy A
Poon, Ivan KH
Hulett, Mark D
author_facet Baxter, Amy A
Poon, Ivan KH
Hulett, Mark D
author_sort Baxter, Amy A
collection PubMed
description Cationic anti-microbial peptides (CAPs) have an important role in host innate defense against pathogens such as bacteria and fungi. Many CAPs including defensins also exhibit selective cytotoxic activity towards mammalian cells via both apoptotic and non-apoptotic processes, and are being investigated as potential anticancer agents. The anti-fungal plant defensin from ornamental tobacco, Nicotiana alata Defensin 1 (NaD1), was recently shown to induce necrotic-like cell death in a number of tumor cell types within 30 min of treatment, at a concentration of 10 μM. NaD1-mediated cell killing within these experimental parameters has been shown to occur via binding to the plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2) in target cells to facilitate membrane destabilization and subsequent lysis. Whether NaD1 is also capable of inducing apoptosis in tumor cells has not been reported previously. In this study, treatment of MM170 (melanoma) and Jurkat T (leukemia) cells with subacute (<10 μM) concentrations of NaD1 over 6–24 h was investigated to determine whether NaD1 could induce cell death via apoptosis. At subacute concentrations, NaD1 did not efficiently induce membrane permeabilization within 30 min, but markedly reduced cell viability over 24 h. In contrast to other CAPs that have been shown to induce apoptosis through caspase activation, dying cells were not sensitive to a pancaspase inhibitor nor did they display caspase activity or DNA fragmentation over the 24 h treatment time. Furthermore, over the 24 h period, cells exhibited necrotic phenotypes and succumbed to membrane permeabilization. These results indicate that the cytotoxic mechanism of NaD1 at subacute concentrations is membranolytic rather than apoptotic and is also likely to be mediated through a PIP2-targeting cell lytic pathway.
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spelling pubmed-52534182017-02-08 The plant defensin NaD1 induces tumor cell death via a non-apoptotic, membranolytic process Baxter, Amy A Poon, Ivan KH Hulett, Mark D Cell Death Discov Article Cationic anti-microbial peptides (CAPs) have an important role in host innate defense against pathogens such as bacteria and fungi. Many CAPs including defensins also exhibit selective cytotoxic activity towards mammalian cells via both apoptotic and non-apoptotic processes, and are being investigated as potential anticancer agents. The anti-fungal plant defensin from ornamental tobacco, Nicotiana alata Defensin 1 (NaD1), was recently shown to induce necrotic-like cell death in a number of tumor cell types within 30 min of treatment, at a concentration of 10 μM. NaD1-mediated cell killing within these experimental parameters has been shown to occur via binding to the plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2) in target cells to facilitate membrane destabilization and subsequent lysis. Whether NaD1 is also capable of inducing apoptosis in tumor cells has not been reported previously. In this study, treatment of MM170 (melanoma) and Jurkat T (leukemia) cells with subacute (<10 μM) concentrations of NaD1 over 6–24 h was investigated to determine whether NaD1 could induce cell death via apoptosis. At subacute concentrations, NaD1 did not efficiently induce membrane permeabilization within 30 min, but markedly reduced cell viability over 24 h. In contrast to other CAPs that have been shown to induce apoptosis through caspase activation, dying cells were not sensitive to a pancaspase inhibitor nor did they display caspase activity or DNA fragmentation over the 24 h treatment time. Furthermore, over the 24 h period, cells exhibited necrotic phenotypes and succumbed to membrane permeabilization. These results indicate that the cytotoxic mechanism of NaD1 at subacute concentrations is membranolytic rather than apoptotic and is also likely to be mediated through a PIP2-targeting cell lytic pathway. Nature Publishing Group 2017-01-23 /pmc/articles/PMC5253418/ /pubmed/28179997 http://dx.doi.org/10.1038/cddiscovery.2016.102 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Baxter, Amy A
Poon, Ivan KH
Hulett, Mark D
The plant defensin NaD1 induces tumor cell death via a non-apoptotic, membranolytic process
title The plant defensin NaD1 induces tumor cell death via a non-apoptotic, membranolytic process
title_full The plant defensin NaD1 induces tumor cell death via a non-apoptotic, membranolytic process
title_fullStr The plant defensin NaD1 induces tumor cell death via a non-apoptotic, membranolytic process
title_full_unstemmed The plant defensin NaD1 induces tumor cell death via a non-apoptotic, membranolytic process
title_short The plant defensin NaD1 induces tumor cell death via a non-apoptotic, membranolytic process
title_sort plant defensin nad1 induces tumor cell death via a non-apoptotic, membranolytic process
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253418/
https://www.ncbi.nlm.nih.gov/pubmed/28179997
http://dx.doi.org/10.1038/cddiscovery.2016.102
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