Investigation into the regulation mechanisms of TRAIL apoptosis pathway by mathematical modeling.

TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in tumor cell lines, suggesting its great potential in cancer therapy. Many components in TRAIL-mediated signaling pathway have been identified, but how they interact with each other to determine the network dynamics and final apoptosis remains elusive. Here we constructed a mathematical model of this pathway, which integrated current available information from related experimental literatures, to make a systematic and quantitative description of the cellular responses to TRAIL stimulation. By applying sensitivity analysis, we identified the key components and reactions that have the highest impact on the network dynamics, and then analyzed the regulatory role of several key players in this pathway. To elucidate the function of TRAIL decoy receptors, we compared the competitive ligand binding hypothesis versus the pre-ligand binding hypothesis. Our results show that the pre-ligand binding hypothesis is more suitable for explaining the fact that over-expression of decoy receptors can inhibit apoptosis potently. These results, together with our investigation on other downstream proteins and feedback loops in this pathway, provide insights into the molecular mechanisms of the TRAILmediated apoptosis pathway.