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Bifurcation analysis of insulin regulated mTOR signalling pathway in cancer cells

Krishnamachari Sriram1

  • 1Centre for Computational Biology, Indraprastha Institute of Information Technology-Delhi, Okhla Phase-III, New Delhi, India. sriramk@iiitd.ac.in.

IET Systems Biology
|September 28, 2018
PubMed

Insights

Metformin reverses the mTOR pathway

Area of Science:

  • Oncology
  • Systems Biology
  • Biophysics

Background:

  • The insulin-induced mTOR signaling pathway is a complex network involved in cancer.
  • This pathway's dynamics are regulated by intricate feedback loops.
  • Metformin has been observed to induce apoptosis in breast cancer cells.

Purpose of the Study:

  • To model and analyze the dynamics of the mTOR signaling pathway.
  • To investigate the effect of metformin on cell proliferation and apoptosis.
  • To understand the molecular mechanisms underlying metformin's action in cancer cells.

Main Methods:

  • Mathematical modeling and bifurcation analysis were employed.
  • The study simulated mTOR pathway dynamics with and without metformin.
  • Specific phosphorylation events and their impact on pathway bistability were analyzed.

Main Results:

  • Metformin negatively regulates PI3K via AMPK-induced IRS1 phosphorylation.
  • This leads to a switch in AKT bistability from S-shaped (proliferation) to Z-shaped (apoptosis).
  • Metformin acts as a circuit breaker, promoting cancer cell apoptosis over proliferation.

Conclusions:

  • Metformin effectively reverses the mTOR network's dynamics towards apoptosis.
  • The study provides insights into the circuit breaker mechanism of metformin.
  • The findings have implications for understanding and manipulating biological network dynamics in cancer therapy.

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