Cellular Automata Modeling of FASL‐Initiated Apoptosis

Abstract

Two strategies for fighting cancer by modulating FASL-induced apoptosis were modeled by 2D-cellular automata. Our models predict that cancer cells can be killed by maximizing the apoptosis via joint suppression of FLIP and IAP inhibitors by siRNA and SMAC proteins, respectively. It was also predicted that the presumed feedback loop CASP3-->CASP9-->|IAP in the intrinsic pathway accelerates the apoptosis, but does not change significantly the concentration of DFF40, the protein that decomposes DNA. The alternative strategy of preventing the killing of the immune system's T-cells, via minimizing their tumor-induced FAS-L apoptosis by overexpression of FLIP and IAP, was also shown to be promising with a predicted considerable synergy action of the two inhibitors. Dual suppression or overexpression of apoptosis inhibitors emerges thus as promising approach in the fight against cancer. Our modeling has also brought some light on the process of turning type-I cells into type-II ones, which emerges as compensatory mechanism in case of damaged or silenced FASL pathway by preserving about the same self-death level at only 10-12% lower performance rate.

Mathematical Models of Death Signaling Networks

“…While the core molecular components regulating apoptosis are shared by all models, variations in molecular circuit designs, components, data, mathematical approaches, and study goals make each model a unique tool to study apoptosis. Most often, molecular mechanisms of apoptosis are mathematically represented using ODEs [ 7 , 21 , 22 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ], Boolean logics [ 34 , 35 , 36 ], and Petri nets [ 16 ]; other computational approaches have also been applied [ 18 , 37 , 38 ].…”

“…Up to this point, we have reviewed mathematical models of apoptosis that use ODEs to describe the mechanism of cell death (apoptosis) regulation. However, other mathematical approaches have been also used to study apoptosis regulation [ 16 , 18 , 34 , 35 , 36 , 37 ]. Several apoptosis models have been developed using a Boolean (logical) approach that can analyze extensive regulatory networks with many molecular components and their interactions [ 34 , 35 , 36 ].…”

“…Agent-based modeling turned out to be a more appropriate approach for modeling the death-inducing signaling complex assembly than an ODE-based model that must describe a large number of intermediate products involved in DISC assembly [ 37 ]. A cellular automata approach has been applied to study apoptosis blocking in the immunological response of T cells by varying the inhibitor actions such as FLIP and IAP [ 18 ]. The model predicts that only joint suppression of both FLIP and IAP apoptosis inhibitors can effectively act to kill cancer cells through apoptosis.…”

“…Different modeling approaches have been already successfully applied to model extensive cell death molecular networks. Ordinary differential equations (ODEs), Boolean logic, pharmacokinetic-pharmacodynamic (PK-PD), Petri nets, agent-based modeling (ABM), cellular automata and hybrid approaches are the common choices available to model molecular mechanisms involved in cell death control, decisions and execution [ 6 , 12 , 13 , 15 , 16 , 17 , 18 , 19 ].…”

Mathematical modeling of apoptosis

“…In addition, bistability of DR-induced apoptosis depending on initial procaspase-8 molecule numbers was demonstrated using an ODE model [72,73]. Besides ODE-based models other approaches have been applied to apoptosis modeling, including boolean modeling [74-77], Bayesian modeling [78], petri nets [79], cellular automata [80,81] and agent-based modeling [15]. …”