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

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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.

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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

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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).

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Authors and Affiliations

  1. Department of Physics and Astronomy, University of Victoria, Victoria, BC, Canada

    Richard M. Schmitz

  2. Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada

    Richard M. Schmitz

  3. Department of Mechanical Engineering, University of Victoria, P.O. Box 1700, STN CSC, Victoria, BC, Canada

    Stephanie M. Willerth

  4. Division of Medical Sciences, University of Victoria, Victoria, BC, Canada

    Stephanie M. Willerth

  5. Department of Electrical Engineering, University of Victoria, Victoria, BC, Canada

    Gerrit van Rensburg

  6. Department of Mathematics and Statistics, University of Victoria, Victoria, BC, Canada

    Roderick Edwards

Authors
  1. Richard M. Schmitz
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  2. Stephanie M. Willerth
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  3. Gerrit van Rensburg
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  4. Roderick Edwards
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Corresponding author

Correspondence to Stephanie M. Willerth.

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Schmitz, R.M., Willerth, S.M., van Rensburg, G. et al. Quantitative Analysis of the Rewiring of Signaling Pathways to Alter Cancer Cell Fate. J. Med. Biol. Eng. 40, 41–52 (2020). https://doi.org/10.1007/s40846-019-00489-4

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  • DOI: https://doi.org/10.1007/s40846-019-00489-4

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