Computational modeling of apoptotic signaling pathways induced by cisplatin

Abstract

BackgroundApoptosis is an essential property of all higher organisms that involves extremely complex signaling pathways. Mathematical modeling provides a rigorous integrative approach for analyzing and understanding such intricate biological systems.ResultsHere, we constructed a large-scale, literature-based model of apoptosis pathways responding to an external stimulus, cisplatin. Our model includes the key elements of three apoptotic pathways induced by cisplatin: death receptor-mediated, mitochondrial, and endoplasmic reticulum-stress pathways. We showed that cisplatin-induced apoptosis had dose- and time-dependent characteristics, and the level of apoptosis was saturated at higher concentrations of cisplatin. Simulated results demonstrated that the effect of the mitochondrial pathway on apoptosis was the strongest of the three pathways. The cross-talk effect among pathways accounted for approximately 25% of the total apoptosis level.ConclusionsUsing this model, we revealed a novel mechanism by which cisplatin induces dose-dependent cell death. Our finding that the level of apoptosis was affected by not only cisplatin concentration, but also by cross talk among pathways provides in silico evidence for a functional impact of system-level characteristics of signaling pathways on apoptosis.

Modeling Mitochondrial Function and Its Role in Disease

“…The combination of this type of mechanistic model with other pathways will be an essential step for understanding apoptosis. One recent effort to do so by Hong and colleagues 31 developed a large-scale literature based model to describe the signaling pathways involved in cisplatin-induced apoptosis. The model suggests that the pathways involve activation of the ER-stress pathway, increased cytosolic calcium and activation of the TNF (tumor necrosis factor) pathway that reduces expression of Bcl-2.…”

Influence of Energy Deficiency on the Molecular Processes of Substantia Nigra Pars Compacta Cell for Understanding Parkinsonian Neurodegeneration: A Comprehensive Biophysical Computational Model

“…The proposed comprehensive single-cell model of SNc dopaminergic neuron consists of ionchannel dynamics (Francis et al, 2013), calcium buffering mechanisms (Francis et al, 2013;Marhl et al, 2000), energy metabolism pathways Wellstead, 2010, 2012), dopamine turnover processes (Tello-Bravo, 2012), LDOPA-uptake mechanisms (Reed et al, 2012), apoptotic pathways (Hong et al, 2012). and molecular pathways involved in PD pathology (Cloutier and Wellstead, 2012) (Figure 1).…”

A Computational Model for Investigating Tumor Apoptosis Induced by Mesenchymal Stem Cell-Derived Secretome

“…The extrinsic and intrinsic pathways we use here are adopted from various sources [8, 10, 24–26] with minor modifications. We integrate the perforin pathway in order to build a comprehensive model that covers all signaling pathways known to be involved in apoptosis induced by MSC secretome.…”

“…All other values are taken from [24]. The superscript “+” indicates forward rate constant and “−” reverse rate constant.…”

“…Previous modeling work on apoptosis itself, such as [21–23], mostly focused on partial signaling pathways. Hong et al [24] proposed a continuous ordinary differential equations (ODE) model for the apoptosis signaling network to study the effect of cisplatin. Even though their comprehensive model included three major pathways involved in cisplatin induced apoptosis, namely, the mitochondrial, death receptor-mediated, and endoplasmic reticulum-stress pathways, it is a single scale model at the molecular level and is not integrated to the other levels of the system.…”