Oscillatory dynamics of p53 pathway in etoposide sensitive and resistant cell lines

Abstract

In this paper, the kinetics of p53 in two cell lines with different degrees of sensitivity to chemotherapeutic drugs is studied. There is much research that has explored the p53 oscillation, but there are few comparisons between cells that are sensitive to drug treatment and those that are not. Here, the kinetics of the p53 system between etoposide-sensitive and etoposide-resistant cell lines in response to different drug doses and different protein synthesis time delays are studied and compared. First, the results showed that time delay is an important condition for p53 oscillation by producing Hopf bifurcation in both the etoposide-sensitive and etoposide-resistant cells. If the protein synthesis time delays are zero, the system cannot oscillate even the dose of the drug increases. Second, the time delay required for producing sustained oscillation in sensitive cells is shorter than the drug-resistant cells. In addition, the p53-Wip1 negative feedback loop in drug-resistant cells is relatively highly strengthened than the drug-sensitive cells. To sum up, p53 oscillation is controlled by time delay, drug dose, and the coupled negative feedback network including p53-mdm2 and p53-wip1. Moreover, in the two different types of cells, the control mechanisms are similar, but there are also differences.

Keywords

• drug-sensitive
• drug-resistant
• oscillation
• time delay
• hopf bifurcation