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Quantitative Analysis of the Rewiring of Signaling Pathways to Alter Cancer Cell Fate

  • Richard M. Schmitz
  • Stephanie M. WillerthEmail author
  • Gerrit van Rensburg
  • Roderick Edwards
Original Article

Abstract

Purpose

Cancer occurs when signaling pathways become unregulated or constitutively activated inside a cell. For example, deregulation of the mitogen activated protein kinase (MAPK) pathway often leads to cancer by promoting uncontrolled cellular proliferation. Chimeric proteins can rewire these signal transduction pathways active in cancer cells by linking activation of the MAPK pathway to activation of the Fas apoptosis pathway, causing the input signal for cell proliferation to be redirected to induce cell death.

Methods

We present here a kinetic model demonstrating how these chimeric proteins can trigger apoptosis upon stimulation of the MAPK pathway. This model consists of ordinary differential equations using rate constants found in literature along with experimental data from previously published work. At a concentration of 1500 nM, the chimeric protein caused a 60% decrease in MAPK activation, causing the cell to transition from a proliferative state to an apoptotic state, validating previous experimental observations. Even at much lower concentrations (e.g. 24 nM), the apoptosis pathway is activated, so the model suggests that cell death may occur even without a direct suppression of the proliferation pathway.

Results and Conclusions

We have developed a quantitative model of caspase activation and its effect on the MAPK pathway in the presence of a chimeric protein, providing insight into a potential mechanism for reprogramming cancer cells.

Keywords

Tyrosine kinases Biochemical simulation Cell signaling Kinetic modeling Reprogramming Cancer 

List of Abbreviations

Csp8

Procaspase-8

Csp*

Activated caspase-8

DED

Death-effecter domain

EGF

Epidermal growth factor

EGFR

Epidermal growth factor receptor

EGFR-Csp8

Phosphorylated EGF ligand and EGFR complex with Csp8 bound

EGFR-P

Phosphorylated EGF ligand and EGFR complex

EGFR-PD

Phosphorylated EGF ligand and EGFR complex with PTD-DED bound

FADD

Fas-associated protein with death domain

LMP1

Latent membrane protein 1

LR

Ligand receptor complex

MAPK

Mitogen-activated protein kinase

MOI

Multiplicity of infection

NGF

Nerve growth factor

PI3 K-Akt

Phosphoinositide 3-kinase-RAC-alpha serine/threonine-protein kinase

PKC

Protein kinase C

PMA

Phorbol-12-myristate-13-acetate

PTB

Phosphotyrosine binding

PTB-DED

Chimeric protein utilizing phosphotyrosine binding (PTB) domain and death-effecter domain (DED)

RTKs

Receptor tyrosine kinases

Shc

Src homoloy 2 domain

TEVP

Tobacco etch virus protease

Notes

Acknowledgements

The authors would like to thank to Dr. Satoshi Yamada and colleagues for supplying us with the equations and parameters for their model as well as Dr. Perry Howard for many helpful conversations, insights and direction. This work was supported by an NSERC URSA award (RS), NSERC Discovery Grants (RE and SMW), and the Canada Research Chairs program (SMW).

Supplementary material

40846_2019_489_MOESM1_ESM.docx (34 kb)
Electronic supplementary material 1 (DOCX 34 kb)

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Copyright information

© Taiwanese Society of Biomedical Engineering 2019

Authors and Affiliations

  1. 1.Department of Physics and AstronomyUniversity of VictoriaVictoriaCanada
  2. 2.Department of Biochemistry and MicrobiologyUniversity of VictoriaVictoriaCanada
  3. 3.Department of Mechanical EngineeringUniversity of VictoriaVictoriaCanada
  4. 4.Division of Medical SciencesUniversity of VictoriaVictoriaCanada
  5. 5.Department of Electrical EngineeringUniversity of VictoriaVictoriaCanada
  6. 6.Department of Mathematics and StatisticsUniversity of VictoriaVictoriaCanada

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