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Open Access Highly Accessed Research article

Computational modeling of apoptotic signaling pathways induced by cisplatin

Ji-Young Hong1, Geun-Hong Kim1, Jun-Woo Kim1, Soon-Sung Kwon1, Eisuke F Sato2, Kwang-Hyun Cho3 and Eun Bo Shim1*

Author Affiliations

1 Department of Mechanical and Biomedical Engineering, Kangwon National University, 192-1, Hyoja 2-dong, Chuncheon, Gangwon-do, 200-701, Republic of Korea

2 Department of Medical Biochemistry, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka, mie 513-8670, Japan

3 Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 305-701, Republic of Korea

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BMC Systems Biology 2012, 6:122  doi:10.1186/1752-0509-6-122

Published: 11 September 2012

Abstract

Background

Apoptosis 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.

Results

Here, 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.

Conclusions

Using 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.

Keywords:
Apoptotic pathways; Cisplatin; Mathematical model