title: Computational modeling of apoptotic signaling pathways induced by cisplatin.
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.
authors.affiliation: Department of Mechanical and Biomedical Engineering, Kangwon National University, 192-1 Hyoja 2-dong, Chuncheon, Gangwon-do 200-701, Republic of Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Hong
authors.forename: Geun-Hong
authors.initials: GH
authors.lastname: Kim
authors.forename: Jun-Woo
authors.initials: JW
authors.lastname: Kim
authors.forename: Soon-Sung
authors.initials: SS
authors.lastname: Kwon
authors.forename: Eisuke F
authors.initials: EF
authors.lastname: Sato
authors.forename: Kwang-Hyun
authors.initials: KH
authors.lastname: Cho
authors.forename: Eun Bo
authors.initials: EB
authors.lastname: Shim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D008954:Models, Biological; D020239:Receptor Cross-Talk / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D049490:Systems Biology; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin