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

Matt W Anderson; Joanna Moss; Robert Szalai; Jon Lane

doi:10.1016/j.isci.2019.01.015

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

Matt W Anderson^*, Joanna Moss, Robert Szalai, Jon Lane

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

21 Citations (Scopus)

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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 language	English
Pages (from-to)	182-193
Number of pages	36
Journal	iScience
Volume	12
Early online date	14 Jan 2019
DOIs	https://doi.org/10.1016/j.isci.2019.01.015
Publication status	Published - 22 Feb 2019

Bibliographical note

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Groups and Themes

Engineering Mathematics Research Group

Keywords

Cancer
Cell Biology
In Silico Biology

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10.1016/j.isci.2019.01.015

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@article{6a91016d4e7e4998825d776c368063ee,

title = "Mathematical Modeling Highlights the Complex Role of AKT in TRAIL-Induced Apoptosis of 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.",

keywords = "Cancer, Cell Biology, In Silico Biology",

author = "Anderson, \{Matt W\} and Joanna Moss and Robert Szalai and Jon Lane",

year = "2019",

month = feb,

day = "22",

doi = "10.1016/j.isci.2019.01.015",

language = "English",

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journal = "iScience",

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TY - JOUR

T1 - Mathematical Modeling Highlights the Complex Role of AKT in TRAIL-Induced Apoptosis of Colorectal Carcinoma Cells

AU - Anderson, Matt W

AU - Moss, Joanna

AU - Szalai, Robert

AU - Lane, Jon

PY - 2019/2/22

Y1 - 2019/2/22

N2 - 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.

AB - 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.

KW - Cancer

KW - Cell Biology

KW - In Silico Biology

UR - https://www.scopus.com/pages/publications/85065772264

U2 - 10.1016/j.isci.2019.01.015

DO - 10.1016/j.isci.2019.01.015

M3 - Article (Academic Journal)

C2 - 30690394

AN - SCOPUS:85065772264

SN - 2589-0042

VL - 12

SP - 182

EP - 193

JO - iScience

JF - iScience

ER -

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

Abstract

Bibliographical note

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

Abstract

Bibliographical note

UN SDGs

Research Groups and Themes

Keywords

Access to Document

Handle.net

Other files and links

Embargoed Document

Fingerprint

Profiles

Professor Jon D Lane

Cite this