Monte Carlo Study Elucidates the Type 1/Type 2 Choice in Apoptotic Death Signaling in Healthy and Cancer Cells

Abstract

Apoptotic cell death is coordinated through two distinct (type 1 and type 2) intracellular signaling pathways. How the type 1/type 2 choice is made remains a central problem in the biology of apoptosis and has implications for apoptosis related diseases and therapy. We study the problem of type 1/type 2 choice in silico utilizing a kinetic Monte Carlo model of cell death signaling. Our results show that the type 1/type 2 choice is linked to deterministic versus stochastic cell death activation, elucidating a unique regulatory control of the apoptotic pathways. Consistent with previous findings, our results indicate that caspase 8 activation level is a key regulator of the choice between deterministic type 1 and stochastic type 2 pathways, irrespective of cell types. Expression levels of signaling molecules downstream also regulate the type 1/type 2 choice. A simplified model of DISC clustering elucidates the mechanism of increased active caspase 8 generation and type 1 activation in cancer cells having increased sensitivity to death receptor activation. We demonstrate that rapid deterministic activation of the type 1 pathway can selectively target such cancer cells, especially if XIAP is also inhibited; while inherent cell-to-cell variability would allow normal cells stay protected.

Kinetic Monte Carlo Study of the Type 1/Type 2 Choice in Apoptosis Elucidates Selective Killing of Cancer Cells under Death Ligand Induction

“…Therefore, type 2 to type 1 transition seems to allow a stochastic--to--deterministic change in apoptotic activation. In certain cancers, such a stochastic--to--deterministic change (through type 2 to type 1 transition) will be possible to achieve by combinatorial treatments, such as by the combined action of TRAIL and XIAP inhibitors [3,14,18]. Incorporation of decoy receptors in our current study introduces additional complexity into the type 1/ type 2 choice problem in apoptotic activation.…”

“…A typical simulation is run for 10 8 MC steps. Kinetic reaction rates (such as kon /koff ) and molecular concentrations were obtained from values reported in the literature (mostly from [27]) [32] and utilized in our previous work [14,15,19,33] (unless specified otherwise). In our studies of cancer cells, concentrations of over--expressed molecules are provided (fold over-expression was defined with respect to concentrations used in simulating apoptosis in healthy cells).…”

“…Results obtained from our computational studies indicated that type 1/type 2 choice is regulated at a systems level, both in healthy and cancer cells. In addition, analysis of our in silico data provided insights [14] into recent experimental studies that explored the type 1/type 2 choice in apoptotic activation. In a recent study, we showed that the concentration of death ligand is a key determinant of type 1/ type 2 choice in healthy cells [15].…”

“…Increased DL concentration resulted in markedly increased apoptosis and also increased activation through the type 1 pathway ( Figure 2). However, the type 1 activation seemed to proceed only after Smac was released from mitochondria and XIAP was inhibited [14,38,39]. In this type 2 assisted type 1 mode of activation, the time to cytochrome c/Smac release exhibited significant stochastic variability mainly due to cell-to-cell stochastic fluctuations in activation of the membrane module.…”

“…In our previous studies, we addressed the problem of understanding systems level regulation of type 1/type 2 choice in apoptotic activation [14,15]. Results obtained from our computational studies indicated that type 1/type 2 choice is regulated at a systems level, both in healthy and cancer cells.…”