Application of bifurcation theory and siRNA-based control signal to restore the proper response of cancer cells to DNA damage

• Published in: Journal of theoretical biology 2016-11, Vol.408, p.213-221
• Main Authors: Kozłowska, Emilia, Puszynski, Krzysztof
• Format: Article
• Language: English
• Subjects: Bifurcation theory; Cell Line, Tumor; DNA Damage; Humans; Models, Theoretical; Neoplasms - pathology; RNA, Small Interfering - pharmacology; Signal Transduction - drug effects; SiRNA; Transduction pathway; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0022-5193; 1095-8541
• DOI: 10.1016/j.jtbi.2016.08.017

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. •We show how the bifurcation theory and siRNA can be used for cancer cells treatment.•Two cancer-specific abnormalities were investigated: Mdm2 over-expression and PTEN silencing.•Bifurcation theory can reveal significant differences in normal and cancer cells dynamics.•These differences can be overcome by siRNA-based control signals.•We show that this can lead to the sensitization of the cancer cells to IR. Additionally healthy cells can be immunized to IR.