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Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes
When clonal populations of human cells are exposed to apoptosis-inducing agents, some cells die and others survive. This fractional killing arises not from mutation but from preexisting, stochastic differences in the levels and activities of proteins regulating apoptosis. Here we examine the propert...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3708725/ https://www.ncbi.nlm.nih.gov/pubmed/23699397 http://dx.doi.org/10.1091/mbc.E12-10-0737 |
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author | Flusberg, Deborah A. Roux, Jérémie Spencer, Sabrina L. Sorger, Peter K. |
author_facet | Flusberg, Deborah A. Roux, Jérémie Spencer, Sabrina L. Sorger, Peter K. |
author_sort | Flusberg, Deborah A. |
collection | PubMed |
description | When clonal populations of human cells are exposed to apoptosis-inducing agents, some cells die and others survive. This fractional killing arises not from mutation but from preexisting, stochastic differences in the levels and activities of proteins regulating apoptosis. Here we examine the properties of cells that survive treatment with agonists of two distinct death receptors, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and anti-FasR antibodies. We find that “survivor” cells are highly resistant to a second ligand dose applied 1 d later. Resistance is reversible, resetting after several days of culture in the absence of death ligand. “Reset” cells appear identical to drug-naive cells with respect to death ligand sensitivity and gene expression profiles. TRAIL survivors are cross-resistant to activators of FasR and vice versa and exhibit an NF-κB–dependent inflammatory phenotype. Remarkably, reversible resistance is induced in the absence of cell death when caspase inhibitors are present and can be sustained for 1 wk or more, also without cell death, by periodic ligand exposure. Thus stochastic differences in cell state can have sustained consequences for sensitivity to prodeath ligands and acquisition of proinflammatory phenotypes. The important role played by periodicity in TRAIL exposure for induction of opposing apoptosis and survival mechanisms has implications for the design of optimal therapeutic agents and protocols. |
format | Online Article Text |
id | pubmed-3708725 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-37087252013-09-30 Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes Flusberg, Deborah A. Roux, Jérémie Spencer, Sabrina L. Sorger, Peter K. Mol Biol Cell Articles When clonal populations of human cells are exposed to apoptosis-inducing agents, some cells die and others survive. This fractional killing arises not from mutation but from preexisting, stochastic differences in the levels and activities of proteins regulating apoptosis. Here we examine the properties of cells that survive treatment with agonists of two distinct death receptors, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and anti-FasR antibodies. We find that “survivor” cells are highly resistant to a second ligand dose applied 1 d later. Resistance is reversible, resetting after several days of culture in the absence of death ligand. “Reset” cells appear identical to drug-naive cells with respect to death ligand sensitivity and gene expression profiles. TRAIL survivors are cross-resistant to activators of FasR and vice versa and exhibit an NF-κB–dependent inflammatory phenotype. Remarkably, reversible resistance is induced in the absence of cell death when caspase inhibitors are present and can be sustained for 1 wk or more, also without cell death, by periodic ligand exposure. Thus stochastic differences in cell state can have sustained consequences for sensitivity to prodeath ligands and acquisition of proinflammatory phenotypes. The important role played by periodicity in TRAIL exposure for induction of opposing apoptosis and survival mechanisms has implications for the design of optimal therapeutic agents and protocols. The American Society for Cell Biology 2013-07-15 /pmc/articles/PMC3708725/ /pubmed/23699397 http://dx.doi.org/10.1091/mbc.E12-10-0737 Text en © 2013 Flusberg et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Flusberg, Deborah A. Roux, Jérémie Spencer, Sabrina L. Sorger, Peter K. Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes |
title | Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes |
title_full | Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes |
title_fullStr | Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes |
title_full_unstemmed | Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes |
title_short | Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes |
title_sort | cells surviving fractional killing by trail exhibit transient but sustainable resistance and inflammatory phenotypes |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3708725/ https://www.ncbi.nlm.nih.gov/pubmed/23699397 http://dx.doi.org/10.1091/mbc.E12-10-0737 |
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