Bcl-2 inhibits apoptosis by increasing the time-to-death and intrinsic cell-to-cell variations in the mitochondrial pathway of cell death

Abstract

BH3 mimetics have been proposed as new anticancer therapeutics. They target anti-apoptotic Bcl-2 proteins, up-regulation of which has been implicated in the resistance of many cancer cells, particularly leukemia and lymphoma cells, to apoptosis. Using probabilistic computational modeling of the mitochondrial pathway of apoptosis, verified by single-cell experimental observations, we develop a model of Bcl-2 inhibition of apoptosis. Our results clarify how Bcl-2 imparts its anti-apoptotic role by increasing the time-to-death and cell-to-cell variability. We also show that although the commitment to death is highly impacted by differences in protein levels at the time of stimulation, inherent stochastic fluctuations in apoptotic signaling are sufficient to induce cell-to-cell variability and to allow single cells to escape death. This study suggests that intrinsic cell-to-cell stochastic variability in apoptotic signaling is sufficient to cause fractional killing of cancer cells after exposure to BH3 mimetics. This is an unanticipated facet of cancer chemoresistance.Electronic supplementary materialThe online version of this article (doi:10.1007/s10495-010-0515-7) contains supplementary material, which is available to authorized users.

Modelling the effect of GRP78 on anti-oestrogen sensitivity and resistance in breast cancer

“…In our deterministic model, we simulate a single cell, and for specified initial conditions, the cell either commits to apoptosis or it does not. In a population of cells, however, a specified treatment will cause some cells to commit to apoptosis and others to live, owing ( presumably) to the fact that protein levels in individual cells are distributed over a range of values [80,81]. Thus, cells with lower levels of BCL2 mito are more likely to commit apoptosis, whereas those with higher levels are less likely to do so.…”

Nonlinear regulation of commitment to apoptosis by simultaneous inhibition of Bcl-2 and XIAP in leukemia and lymphoma cells

“…We showed previously that the combined effects of (a) allor-none activation of caspase 9 and 3 at the single cell level, and (b) cell-to-cell fluctuations lead to bi-modal probability distributions for activated caspase 9 and 3 [9]. This study shows that the combined effect of higher Bcl-2 and XIAP levels leads to efficient suppression of cell death, and results in an increase in the time-to-death and its cell-to-cell variability.…”

“…3C), again confirming the non-linear effect of XIAP inhibition on sensitivity to the BH3 mimetic. Importantly, non-cancerous HEK293 cells, which are resistant to cell death induced by HA14-1 [9], were not sensitized by embelin (3d). Similarly, in peripheral blood mononuclear cells (PBMCs), obtained from healthy individuals, treatment with embelin did not enhance HA14-1-induced apoptosis (Fig.…”

“…The advantage of in silico models of cellular systems is that one can selectively study the behavior of specific pathways, reducing the complexity of biological systems, and thus test concepts that are otherwise difficult to verify experimentally [10,19]. Recent developments in the field of computational systems biology have paved the way to important new discoveries pertinent to cancer therapy [9,20,21]. Mathematical approaches range from models of cancer epidemiology [22] or models reproducing the dynamics of accumulation of genetic changes during tumorigenesis [23], through computational tools for predicting response of cancer cells to treatment [24], up to early stage models for design of patient-specific immunotherapy [25], and all provide invaluable insights into cancer biology.…”

MicroRNAs mediate the cardioprotective effect of angiotensin-converting enzyme inhibition in acute kidney injury

“…BCL-2 has been shown to inhibit apoptosis in cardiac cells (35,49) and other cell types (22,46). A previous study (49) has demonstrated BCL-2 as a direct target of microRNA-1 using luciferase reporter experiments and also reported a downregulatory effect of microRNA-1 on BCL-2 expression.…”