Abstract
Abstract Fractional killing of a population of cancer cells is often linked to cell-to-cell variability due to stochastic gene expression and fluctuations in protein levels. We found that mitochondria abundance is a major source of cell-to-cell variability that determines the fraction of cells that live or die in response to TNF-related apoptosis-inducing ligand (TRAIL). We show that the IC50 of TRAIL of clonogenic cancer cell populations correlates with mitochondria abundance, and cell-to-cell variability in mitochondria abundance controls up to 40% of the response to TRAIL. Our coarse-grained quantitative model of apoptosis reveals that increasing the mitochondrial surface area decreases the density of proapoptotic Bax pores, which in turn decreases the sensitivity of cells to TRAIL. We demonstrate that the clinically relevant small-molecule inhibitor of antiapoptotic Bcl-2 proteins ABT-263 reduces the IC50 of TRAIL by reducing the contribution of mitochondria to variability in apoptosis. Citation Format: Luis C. Santos, Robert Vogel, Jerry E. Chipuk, Marc Birtwistle, Gustavo Stolovitzky, Pablo Meyer. Origins of fractional control in regulated cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 375.
Published Version
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