Quantitative Analysis of the Rewiring of Signaling Pathways to Alter Cancer Cell Fate

Autor: Gerrit van Rensburg, Richard M. Schmitz, Roderick Edwards, Stephanie M. Willerth
Rok vydání: 2019
Předmět:
Zdroj: Journal of Medical and Biological Engineering. 40:41-52
ISSN: 2199-4757
1609-0985
DOI: 10.1007/s40846-019-00489-4
Popis: Cancer occurs when signaling pathways become unregulated or constitutively activated inside a cell. For example, deregulation of the mitogen activated protein kinase (MAPK) pathway often leads to cancer by promoting uncontrolled cellular proliferation. Chimeric proteins can rewire these signal transduction pathways active in cancer cells by linking activation of the MAPK pathway to activation of the Fas apoptosis pathway, causing the input signal for cell proliferation to be redirected to induce cell death. We present here a kinetic model demonstrating how these chimeric proteins can trigger apoptosis upon stimulation of the MAPK pathway. This model consists of ordinary differential equations using rate constants found in literature along with experimental data from previously published work. At a concentration of 1500 nM, the chimeric protein caused a 60% decrease in MAPK activation, causing the cell to transition from a proliferative state to an apoptotic state, validating previous experimental observations. Even at much lower concentrations (e.g. 24 nM), the apoptosis pathway is activated, so the model suggests that cell death may occur even without a direct suppression of the proliferation pathway. We have developed a quantitative model of caspase activation and its effect on the MAPK pathway in the presence of a chimeric protein, providing insight into a potential mechanism for reprogramming cancer cells.
Databáze: OpenAIRE
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