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Stochastic fluctuations in apoptotic threshold of tumour cells can enhance apoptosis and combat fractional killing
Fractional killing, which is a significant impediment to successful chemotherapy, is observed even in a population of genetically identical cancer cells exposed to apoptosis-inducing agents. This phenomenon arises not from genetic mutation but from cell-to-cell variation in the activation timing and...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062090/ https://www.ncbi.nlm.nih.gov/pubmed/32257298 http://dx.doi.org/10.1098/rsos.190462 |
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author | Qiu, Baohua Zhou, Tianshou Zhang, Jiajun |
author_facet | Qiu, Baohua Zhou, Tianshou Zhang, Jiajun |
author_sort | Qiu, Baohua |
collection | PubMed |
description | Fractional killing, which is a significant impediment to successful chemotherapy, is observed even in a population of genetically identical cancer cells exposed to apoptosis-inducing agents. This phenomenon arises not from genetic mutation but from cell-to-cell variation in the activation timing and level of the proteins that regulates apoptosis. To understand the mechanism behind the phenomenon, we formulate complex fractional killing processes as a first-passage time (FPT) problem with a stochastically fluctuating boundary. Analytical calculations are performed for the FPT distribution in a toy model of stochastic p53 gene expression, where the cancer cell is killed only when the p53 expression level crosses an active apoptotic threshold. Counterintuitively, we find that threshold fluctuations can effectively enhance cellular killing by significantly decreasing the mean time that the p53 protein reaches the threshold level for the first time. Moreover, faster fluctuations lead to the killing of more cells. These qualitative results imply that fluctuations in threshold are a non-negligible stochastic source, and can be taken as a strategy for combating fractional killing of cancer cells. |
format | Online Article Text |
id | pubmed-7062090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | The Royal Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-70620902020-03-31 Stochastic fluctuations in apoptotic threshold of tumour cells can enhance apoptosis and combat fractional killing Qiu, Baohua Zhou, Tianshou Zhang, Jiajun R Soc Open Sci Mathematics Fractional killing, which is a significant impediment to successful chemotherapy, is observed even in a population of genetically identical cancer cells exposed to apoptosis-inducing agents. This phenomenon arises not from genetic mutation but from cell-to-cell variation in the activation timing and level of the proteins that regulates apoptosis. To understand the mechanism behind the phenomenon, we formulate complex fractional killing processes as a first-passage time (FPT) problem with a stochastically fluctuating boundary. Analytical calculations are performed for the FPT distribution in a toy model of stochastic p53 gene expression, where the cancer cell is killed only when the p53 expression level crosses an active apoptotic threshold. Counterintuitively, we find that threshold fluctuations can effectively enhance cellular killing by significantly decreasing the mean time that the p53 protein reaches the threshold level for the first time. Moreover, faster fluctuations lead to the killing of more cells. These qualitative results imply that fluctuations in threshold are a non-negligible stochastic source, and can be taken as a strategy for combating fractional killing of cancer cells. The Royal Society 2020-02-19 /pmc/articles/PMC7062090/ /pubmed/32257298 http://dx.doi.org/10.1098/rsos.190462 Text en © 2020 The Authors. http://creativecommons.org/licenses/by/4.0/ Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited. |
spellingShingle | Mathematics Qiu, Baohua Zhou, Tianshou Zhang, Jiajun Stochastic fluctuations in apoptotic threshold of tumour cells can enhance apoptosis and combat fractional killing |
title | Stochastic fluctuations in apoptotic threshold of tumour cells can enhance apoptosis and combat fractional killing |
title_full | Stochastic fluctuations in apoptotic threshold of tumour cells can enhance apoptosis and combat fractional killing |
title_fullStr | Stochastic fluctuations in apoptotic threshold of tumour cells can enhance apoptosis and combat fractional killing |
title_full_unstemmed | Stochastic fluctuations in apoptotic threshold of tumour cells can enhance apoptosis and combat fractional killing |
title_short | Stochastic fluctuations in apoptotic threshold of tumour cells can enhance apoptosis and combat fractional killing |
title_sort | stochastic fluctuations in apoptotic threshold of tumour cells can enhance apoptosis and combat fractional killing |
topic | Mathematics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062090/ https://www.ncbi.nlm.nih.gov/pubmed/32257298 http://dx.doi.org/10.1098/rsos.190462 |
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