Open AccessStochastic fluctuations in apoptotic threshold of tumour cells can enhance apoptosis and combat fractional killing
Author(s) -
Baohua Qiu,
Tianshou Zhou,
Jiajun Zhang
Publication year - 2020
Publication title -
royal society open science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.84
H-Index - 51
ISSN - 2054-5703
DOI - 10.1098/rsos.190462
Subject(s) - apoptosis , population , cancer cell , mutation , cell , biology , microbiology and biotechnology , physics , cancer , gene , genetics , medicine , environmental health
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.