A Novel Mathematical Model of Targeted Cancer Therapy along p53 Proteasomal Degradation Pathways

Abstract

Overzealous MDM2-mediated ubiquitination of p53 characterizesand sustains over 50% of all human cancers. Successful targeted cancer therapyhinges on a thorough understanding of the ubiquitination process.Unfortunately, current steady-state enzyme kinetic models fail to accuratelydescribe the ubiquitin-proteasome system, due to the assumption that the enzyme(E3 ligase) is expressed at infinitesimally smaller concentrations than thesubstrates (E2 conjugase and target protein). This limitation of the quasi-steadystate assumption prohibits the use of steady-state models when analyzing thecancerous consequences of extreme ubiquitin-ligase overexpression. This paperderives a novel non-steady-state mathematical model of ternary complex enzymekinetics, which can be used to simulate the behavioral response of theubiquitin-proteasome system to specific variations in the cellularconcentrations of targeted the E2 conjugase, E3 ligase, and target protein.Computer simulations of the model were used to study the effects of E2D3 andMDM2 concentrations on the rates of p53 ubiquitination at differenttemperatures. At each temperature, it was observed that the ubiquitin-ligaseMDM2 accelerates the dangerous degradation process, while the ubiquitinconjugating-enzyme E2D3 inhibits it. It was also discovered that E2D3 is a moreeffective inhibitor of p53 ubiquitination at higher body temperatures, whereas MDM2 is then a less-effective catalyst. The derived model therefore suggests MDM2 as a prospective target for cancer therapy. In addition, the findings of this project propose recombinant E2D3 as a new promising protein-basedanticancer drug and a potential tumor suppressor protein. The mathematical model successfully reproduced the experimentally observed p53-MDM2 interaction. Further in vivo experimentation is necessary for additional validation of thecomputational results. The derived model can suggest new therapeutic solutions for decreasing the harmful effects of many human cancers, bacterial infections,and inflammatory diseases (such as rheumatoid arthritis) characterized by an overzealous ubiquitin-proteasome system.