Mathematical Modeling Highlights the Complex Role of AKT in TRAIL-Induced Apoptosis of Colorectal Carcinoma Cells

Matthew W. Anderson*, Joanna Moss, Robert Szalai, Jon Lane

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

4 Citations (Scopus)
190 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)182-193
Number of pages36
JournaliScience
Volume12
Early online date14 Jan 2019
DOIs
Publication statusPublished - 22 Feb 2019

Bibliographical note

Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

Keywords

  • Cancer
  • Cell Biology
  • In Silico Biology

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