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

TL;DR

This paper uses computational modeling and experiments to show that Bcl-2 prolongs cell death timing and increases variability among cells in the mitochondrial apoptosis pathway, contributing to cancer cell resistance.

Contribution

It provides a detailed model explaining how Bcl-2 inhibits apoptosis by increasing time-to-death and cell-to-cell variability, highlighting stochastic fluctuations as a key factor.

Findings

Bcl-2 increases time-to-death in apoptosis.

Bcl-2 enhances cell-to-cell variability.

Stochastic fluctuations enable some cells to escape 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.