1. Application of bifurcation theory and siRNA-based control signal to restore the proper response of cancer cells to DNA damage
- Author
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Krzysztof Puszynski and Emilia Kozłowska
- Subjects
0301 basic medicine ,Statistics and Probability ,Small interfering RNA ,DNA damage ,medicine.medical_treatment ,Biology ,Bioinformatics ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Bifurcation theory ,Cell Line, Tumor ,Neoplasms ,Modelling and Simulation ,Immunology and Microbiology(all) ,SiRNA ,medicine ,Humans ,RNA, Small Interfering ,Medicine(all) ,General Immunology and Microbiology ,Agricultural and Biological Sciences(all) ,Biochemistry, Genetics and Molecular Biology(all) ,Applied Mathematics ,Dynamics (mechanics) ,Cancer ,General Medicine ,Models, Theoretical ,medicine.disease ,Cell biology ,Radiation therapy ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Modeling and Simulation ,Transduction pathway ,Cancer cell ,sense organs ,Tumor Suppressor Protein p53 ,General Agricultural and Biological Sciences ,DNA Damage ,Signal Transduction - Abstract
Many diseases with a genetic background such as some types of cancer are caused by damage in the p53 signaling pathway. The damage changes the system dynamics providing cancer cells with resistance to therapy such as radiation therapy. The change can be observed as the difference in bifurcation diagrams and equilibria type and location between normal and damaged cells, and summarized as the changes of the mathematical model parameters and following changes of the eigenvalues of Jacobian matrix. Therefore a change in other model parameters, such as mRNA degradation rates, may restore the proper eigenvalues and by that proper system dynamics. From the biological point of view, the change of mRNA degradation rate can be achieved by application of the small interfering RNA (siRNA). Here, we propose a general mathematical framework based on the bifurcation theory and siRNA-based control signal in order to study how to restore the proper response of cells with damaged p53 signaling pathway to therapy by using ionizing radiation (IR) therapy as an example. We show the difference between the cells with normal p53 signaling pathway and cells with abnormalities in the negative (as observed in SJSA-1 cell line) or positive (as observed in MCF-7 or PNT1a cell lines) feedback loop. Then we show how the dynamics of these cells can be restored to normal cell dynamics by using selected siRNA.
- Published
- 2016
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