Monte Carlo study elucidates the type 1/type 2 choice in apoptotic death signaling in normal and cancer cells

TL;DR

This study uses a kinetic Monte Carlo model to investigate how cells choose between type 1 and type 2 apoptotic pathways, revealing key regulatory factors and potential therapeutic strategies for cancer treatment.

Contribution

It introduces a computational model linking pathway choice to deterministic and stochastic activation, highlighting caspase 8 levels and DISC clustering as regulatory mechanisms.

Findings

Caspase 8 level determines pathway choice.

Cancer cells show increased type 1 activation due to DISC clustering.

Inhibiting XIAP enhances selective targeting of 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 fundamental 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 those cancer cells, especially if XIAP is also inhibited; while inherent cell-to-cell variability would allow normal cells stay protected.