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Cell survival following direct executioner-caspase activation

Executioner-caspase activation has been considered a point-of-no-return in apoptosis. However, numerous studies report survival from caspase activation after treatment with drugs or radiation. An open question is whether cells can recover from direct caspase activation without pro-survival stress re...

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Autores principales: Nano, Maddalena, Mondo, James A., Harwood, Jacob, Balasanyan, Varuzhan, Montell, Denise J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942801/
https://www.ncbi.nlm.nih.gov/pubmed/36669100
http://dx.doi.org/10.1073/pnas.2216531120
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author Nano, Maddalena
Mondo, James A.
Harwood, Jacob
Balasanyan, Varuzhan
Montell, Denise J.
author_facet Nano, Maddalena
Mondo, James A.
Harwood, Jacob
Balasanyan, Varuzhan
Montell, Denise J.
author_sort Nano, Maddalena
collection PubMed
description Executioner-caspase activation has been considered a point-of-no-return in apoptosis. However, numerous studies report survival from caspase activation after treatment with drugs or radiation. An open question is whether cells can recover from direct caspase activation without pro-survival stress responses induced by drugs. To address this question, we engineered a HeLa cell line to express caspase-3 inducibly and combined it with a quantitative caspase activity reporter. While high caspase activity levels killed all cells and very low levels allowed all cells to live, doses of caspase activity sufficient to kill 15 to 30% of cells nevertheless allowed 70 to 85% to survive. At these doses, neither the rate, nor the peak level, nor the total amount of caspase activity could accurately predict cell death versus survival. Thus, cells can survive direct executioner-caspase activation, and variations in cellular state modify the outcome of potentially lethal caspase activity. Such heterogeneities may underlie incomplete tumor cell killing in response to apoptosis-inducing cancer treatments.
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spelling pubmed-99428012023-02-22 Cell survival following direct executioner-caspase activation Nano, Maddalena Mondo, James A. Harwood, Jacob Balasanyan, Varuzhan Montell, Denise J. Proc Natl Acad Sci U S A Biological Sciences Executioner-caspase activation has been considered a point-of-no-return in apoptosis. However, numerous studies report survival from caspase activation after treatment with drugs or radiation. An open question is whether cells can recover from direct caspase activation without pro-survival stress responses induced by drugs. To address this question, we engineered a HeLa cell line to express caspase-3 inducibly and combined it with a quantitative caspase activity reporter. While high caspase activity levels killed all cells and very low levels allowed all cells to live, doses of caspase activity sufficient to kill 15 to 30% of cells nevertheless allowed 70 to 85% to survive. At these doses, neither the rate, nor the peak level, nor the total amount of caspase activity could accurately predict cell death versus survival. Thus, cells can survive direct executioner-caspase activation, and variations in cellular state modify the outcome of potentially lethal caspase activity. Such heterogeneities may underlie incomplete tumor cell killing in response to apoptosis-inducing cancer treatments. National Academy of Sciences 2023-01-20 2023-01-24 /pmc/articles/PMC9942801/ /pubmed/36669100 http://dx.doi.org/10.1073/pnas.2216531120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Nano, Maddalena
Mondo, James A.
Harwood, Jacob
Balasanyan, Varuzhan
Montell, Denise J.
Cell survival following direct executioner-caspase activation
title Cell survival following direct executioner-caspase activation
title_full Cell survival following direct executioner-caspase activation
title_fullStr Cell survival following direct executioner-caspase activation
title_full_unstemmed Cell survival following direct executioner-caspase activation
title_short Cell survival following direct executioner-caspase activation
title_sort cell survival following direct executioner-caspase activation
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942801/
https://www.ncbi.nlm.nih.gov/pubmed/36669100
http://dx.doi.org/10.1073/pnas.2216531120
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