Your browser does not support JavaScript!
http://iet.metastore.ingenta.com
1887

access icon free Bifurcation analysis of insulin regulated mTOR signalling pathway in cancer cells

© The Institution of Engineering and Technology
Received 09/01/2018, Accepted 12/04/2018, Revised 01/04/2018, Published 26/04/2018

Insulin induced mTOR signalling pathway is a complex network implicated in many types of cancers. The molecular mechanism of this pathway is highly complex and the dynamics is tightly regulated by intricate positive and negative feedback loops. In breast cancer cell lines, metformin has been shown to induce phosphorylation at specific serine sites in insulin regulated substrate of mTOR pathway that results in apoptosis over cell proliferation. The author models and performs bifurcation analysis to simulate cell proliferation and apoptosis in mTOR signalling pathway to capture the dynamics both in the presence and absence of metformin in cancer cells. Metformin is shown to negatively regulate PI3K through AMPK induced IRS1 phosphorylation and this brings about a reversal of AKT bistablity in codimension-1 bifurcation diagram from S-shaped, related to cell proliferation in the absence of drug metformin, to Z-shaped, related to apoptosis in the presence of drug metformin. The author hypothesises and explains how this negative regulation acts a circuit breaker, as a result of which mTOR network favours apoptosis of cancer cells over its proliferation. The implication of reversing the shape of bistable dynamics from S to Z or vice-versa in biological networks in general is discussed.

Inspec keywords: biochemistry; drugs; enzymes; cancer; cellular biophysics; molecular biophysics; biomedical materials; bifurcation

Other keywords: insulin regulated mTOR signalling pathway; intricate positive feedback loops; breast cancer cell lines; AMPK induced IRS1 phosphorylation; insulin regulated substrate; negative feedback loops; cancer cells; mTOR network; PI3K; bifurcation analysis; drug metformin; cell proliferation; codimension-1 bifurcation diagram; AKT bistablity

Subjects: Cellular biophysics; Patient care and treatment; Nonlinear dynamical systems and bifurcations; Physical chemistry of biomolecular solutions and condensed states; Biomolecular dynamics, molecular probes, molecular pattern recognition; Biomedical materials

References

    1. 1)
      • 11. Grabiner, B.C., Nardi, V., Birsoy, K., et al: ‘A diverse array of cancer-associated mTOR mutations are hyperactivating and can predict rapamycin sensitivity’, Cancer Discov., 2014, 4, (5), pp. 554–563.
    2. 2)
      • 19. Kholodenko, B.N.: ‘Cell signalling dynamics in time and space’, Nat. Rev. Mol. Cell Biol., 2006, 7, (3), pp. 165–176.
    3. 3)
      • 4. Philippe, G., Le Marchand-Brustel, Y., Tanti, J.F.: ‘Positive and negative regulation of insulin signaling through IRS-1 phosphorylation’, Biochimie., 2005, 87, pp. 99–109.
    4. 4)
      • 13. Ablooglu, A.J., Kohanski, R.A., et al: ‘Activation of the insulin receptors kinase domain changes the rate-determining step of substrate phosphorylation’, Biochemistry, 2001, 40, pp. 504–513.
    5. 5)
      • 16. Cherry, J.L., Adler, F.R.: ‘How to make a biological switch’, J. Theor. Biol., 2000, 203, (2), pp. 117–133.
    6. 6)
      • 24. Ferrell, J.E.Jr., Ha, S.H.: ‘Ultrasensitivity part III: cascades, bistable switches, and oscillators’, Trends Biochem. Sci., 2014, 39, (12), pp. 612–618.
    7. 7)
      • 32. Nguyen, L.N., Kholodenko, B.N.: ‘Feedback regulation in cell signalling: lesson for cancer therapeutics’, Sem. Cell Dev. Biol., 2016, 50, pp. 85–94.
    8. 8)
      • 2. Sulaimanov, N., Klose, M., Busch, H., et al: ‘Understanding the mTOR signalling pathway via mathematical modeling’, WIREs Syst. Bio. Med., 2017, 9, pp. 1–18.
    9. 9)
      • 5. Zakikhani, M., Blouin, M., Piura, E., et al: ‘Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells’, Breast Cancer Res. Treat., 2010, 123, (1), pp. 271–279.
    10. 10)
      • 28. Strogatz, S.H.: ‘Nonlinear dynamics and chaos: with applications to physics, biology, chemistry, and engineering’ (Chapman Hall, CRC Press, Cambridge, 2014, 2nd edn.).
    11. 11)
      • 18. Guertin, D.A., Sabatini, D.M.: ‘Defining the role of mTOR in cancer’, Cancer Cell., 2007, 12, pp. 9–22.
    12. 12)
      • 10. Zoncu, R., Efeyan, A., Sabatini, D.M.: ‘mTOR: from growth signal integration to cancer, diabetes and ageing’, Nat. Rev. Mol. Cell Biol., 2011, 12, pp. 21–35.
    13. 13)
      • 29. Zakikhani, M., Dowling, R., Fantus, I.G., et al: ‘Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells’, Cancer Res., 2006, 66, pp. 10269–10273.
    14. 14)
      • 8. Pollak, M.N.: ‘Investigating metformin for cancer prevention and treatment: the end of the beginning’, Cancer Discov., 2012, 2, pp. 778–790.
    15. 15)
      • 23. Ferrell, J.E.Jr., Ha, S.H.: ‘Ultrasensitivity part II: multisite phosphorylation, stoichiometric inhibitors, and positive feedback’, Trends Biochem. Sci., 2014, 39, (11), pp. 556–569.
    16. 16)
      • 17. Laplante, M., Sabatini, D.M.: ‘mTOR signaling at a glance’, J. Cell Sci., 2009, 122, pp. 3589–3594.
    17. 17)
      • 27. Tyson, J.J., Chen, K.C., Novak, B.: ‘Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell’, Curr. Opin. Cell Biol., 2003, 15, (2), pp. 221–231.
    18. 18)
      • 15. Sriram, K., Rodriguez-Fernandez, M., Doyle III, F.J.: ‘A detailed modular analysis of heat-shock protein dynamics under acute stress and its implication in anxiety disorders’, PLoS ONE, 2012, e42958, pp. 1–15.
    19. 19)
      • 7. Pollak, M.: ‘Insulin and insulin-like growth factor signalling in neoplasia’, Nat. Rev. Cancer., 2008, 8, pp. 915–928.
    20. 20)
      • 20. Ermentrout, B.: ‘Simulating, analyzing, and animating dynamical systems: a guide to xppaut for researchers and students’ (Society for Industrial and Applied Mathematics (SIAM), Philadelphia, USA, 2002). Available at www.math.pitt.edu/%7Ebard/xpp/xpp.html.
    21. 21)
      • 12. Birsoy, K., Sabatini, D.M., Possemato, R.: ‘Targeting cancer metabolism: a bedside lesson’, Nat. Med., 2012, 18, (7), pp. 1022–1023.
    22. 22)
      • 3. Araujo, R.P., Liotta, L.A., Petricoin, E.F.: ‘Proteins, drug targets and the mechanisms they control: the simple truth about complex networks’, Nature Rev. Drug Discov., 2007, 6, pp. 871–880.
    23. 23)
      • 31. Sauro, H.M., Kholodenko, B.N.: ‘Quantitative analysis of signalling networks’, Prog. Biophys. Mol. Bio., 2004, 86, pp. 5–43.
    24. 24)
      • 22. Ferrell, J.E.Jr., Ha, S.H.: ‘Ultrasensitivity part I: michaelian responses and zero-order ultrasensitivity’, Trends Biochem. Sci., 2014, 39, (10), pp. 496–503.
    25. 25)
      • 34. Rozengurt, E., Soares, H.P., Sinnet-Smith, J.: ‘Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequences leading to drug resistance’, Mol. Cancer Ther., 2014, 13, (11), pp. 2477–2488.
    26. 26)
      • 30. Soares, H.P., Ni, Y., Kisfalvi, K., et al: ‘Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells’, PLoS ONE, 2013, 8, pp. 57289.
    27. 27)
      • 25. Thomas, R.: ‘Laws for the dynamics of regulatory networks’, Int. J. Dev. Biol., 1998, 42, pp. 479–485.
    28. 28)
      • 21. Sensse, A., Eiswirth, M.: ‘Feedback loops for chaos in activator-inhibitor systems’, J. Chem. Phys., 2005, 122, (4), p. 044516–20.
    29. 29)
      • 36. Sarbassov, D.D., Ali, S.M., Sengupta, S., et al: ‘Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB’, Mol. Cell, 2006, 22, (2), pp. 159–168.
    30. 30)
      • 14. Tzatsos, A., Tscichlis, P.N.: ‘Energy depletion inhibits phosphatidylinositol 3-kinase/AKT signaling and induces apoptosis via AMP-activated protein kinase-dependent phosphorylation of IRS1 at ser-794’, J. Biol. Chem., 2007, 282, pp. 18069–18082.
    31. 31)
      • 26. Alon, U: ‘An introduction to systems biology, design principles of biological circuits’ (CRC Press, Taylor and Francis Group, Boca Raton, FL, USA, 2006).
    32. 32)
      • 35. Alalem, M., Ray, A., Ray, B.K.: ‘Metformin induces degradation of mTOR protein in breast cancer cells’, Cancer Med., 2016, 5, (11), pp. 3194–3204.
    33. 33)
      • 33. Sturm, O.E., Orton, R., Grindlay, J., et al: ‘The mammalian MAPK/ERK pathway exhibits properties of negative feedback amplifier’, Sci. Signal, 2010, 3, pp. 1–7.
    34. 34)
      • 9. Saxton, R.A., Sabatini, D.M.: ‘mTOR signaling in growth, metabolism, and disease’, Cell., 2017, 168, pp. 960–976.
    35. 35)
      • 6. Dowling, R.J., Zakikhani, M., Fantus, I.G., et al: ‘Metformin inhibits mammalian target of rapamycin dependent translation initiation in breast cancer cells’, Cancer Res., 2007, 67, pp. 10804–10812.
    36. 36)
      • 1. Efeyan, A., Sabatini, N.M.: ‘mTOR and cancer: many loops in one pathway’, Curr. Opin. Cell. Biol., 2010, 22, pp. 169–176.
http://iet.metastore.ingenta.com/content/journals/10.1049/iet-syb.2018.0003
Loading

Related content

content/journals/10.1049/iet-syb.2018.0003
pub_keyword,iet_inspecKeyword,pub_concept
6
6
Loading
Print this page
This is a required field
Please enter a valid email address