Mathematical modelling highlights the complex role of AKT in TRAIL-induced apoptosis of HCT116 colorectal carcinoma cells

Abstract

Protein kinase B/AKT is a highly connected protein involved in a range of signaling pathways. Although it is known to regulate several proteins in the apoptotic pathway, its system level effects remain poorly understood. We investigated the dynamic interactions between AKT and key apoptotic proteins, and constructed a deterministic Ordinary Differential Equation protein interaction model of extrinsic apoptosis. Incorporating AKT and its indirect inhibitor, PTEN, this was used to generate predictions of system dynamics. Using eigenanalysis, we identified AKT and cytochrome c as the protein species most sensitive to perturbations. Cell death assays in Type II HCT116 colorectal carcinoma cells revealed a tendency towards Type I cell death behavior in the XIAP-/- background, with cells displaying accelerated TRAIL-induced apoptosis. Finally, AKT inhibition experiments implicated AKT and not PTEN in influencing apoptotic proteins during early phases of TRAIL-induced apoptosis.