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Bifurcation analysis of insulin regulated mTOR signalling pathway in cancer cells

Bifurcation analysis of insulin regulated mTOR signalling pathway in cancer cells

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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.

References

    1. 1)
      • 1. Efeyan, A., Sabatini, N.M.: ‘mTOR and cancer: many loops in one pathway’, Curr. Opin. Cell. Biol., 2010, 22, pp. 169176.
    2. 2)
      • 2. Sulaimanov, N., Klose, M., Busch, H., et al: ‘Understanding the mTOR signalling pathway via mathematical modeling’, WIREs Syst. Bio. Med., 2017, 9, pp. 118.
    3. 3)
      • 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. 871880.
    4. 4)
      • 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. 99109.
    5. 5)
      • 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. 271279.
    6. 6)
      • 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. 1080410812.
    7. 7)
      • 7. Pollak, M.: ‘Insulin and insulin-like growth factor signalling in neoplasia’, Nat. Rev. Cancer., 2008, 8, pp. 915928.
    8. 8)
      • 8. Pollak, M.N.: ‘Investigating metformin for cancer prevention and treatment: the end of the beginning’, Cancer Discov., 2012, 2, pp. 778790.
    9. 9)
      • 9. Saxton, R.A., Sabatini, D.M.: ‘mTOR signaling in growth, metabolism, and disease’, Cell., 2017, 168, pp. 960976.
    10. 10)
      • 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. 2135.
    11. 11)
      • 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. 554563.
    12. 12)
      • 12. Birsoy, K., Sabatini, D.M., Possemato, R.: ‘Targeting cancer metabolism: a bedside lesson’, Nat. Med., 2012, 18, (7), pp. 10221023.
    13. 13)
      • 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. 504513.
    14. 14)
      • 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. 1806918082.
    15. 15)
      • 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. 115.
    16. 16)
      • 16. Cherry, J.L., Adler, F.R.: ‘How to make a biological switch’, J. Theor. Biol., 2000, 203, (2), pp. 117133.
    17. 17)
      • 17. Laplante, M., Sabatini, D.M.: ‘mTOR signaling at a glance’, J. Cell Sci., 2009, 122, pp. 35893594.
    18. 18)
      • 18. Guertin, D.A., Sabatini, D.M.: ‘Defining the role of mTOR in cancer’, Cancer Cell., 2007, 12, pp. 922.
    19. 19)
      • 19. Kholodenko, B.N.: ‘Cell signalling dynamics in time and space’, Nat. Rev. Mol. Cell Biol., 2006, 7, (3), pp. 165176.
    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)
      • 21. Sensse, A., Eiswirth, M.: ‘Feedback loops for chaos in activator-inhibitor systems’, J. Chem. Phys., 2005, 122, (4), p. 04451620.
    22. 22)
      • 22. Ferrell, J.E.Jr., Ha, S.H.: ‘Ultrasensitivity part I: michaelian responses and zero-order ultrasensitivity’, Trends Biochem. Sci., 2014, 39, (10), pp. 496503.
    23. 23)
      • 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. 556569.
    24. 24)
      • 24. Ferrell, J.E.Jr., Ha, S.H.: ‘Ultrasensitivity part III: cascades, bistable switches, and oscillators’, Trends Biochem. Sci., 2014, 39, (12), pp. 612618.
    25. 25)
      • 25. Thomas, R.: ‘Laws for the dynamics of regulatory networks’, Int. J. Dev. Biol., 1998, 42, pp. 479485.
    26. 26)
      • 26. Alon, U: ‘An introduction to systems biology, design principles of biological circuits’ (CRC Press, Taylor and Francis Group, Boca Raton, FL, USA, 2006).
    27. 27)
      • 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. 221231.
    28. 28)
      • 28. Strogatz, S.H.: ‘Nonlinear dynamics and chaos: with applications to physics, biology, chemistry, and engineering’ (Chapman Hall, CRC Press, Cambridge, 2014, 2nd edn.).
    29. 29)
      • 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. 1026910273.
    30. 30)
      • 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.
    31. 31)
      • 31. Sauro, H.M., Kholodenko, B.N.: ‘Quantitative analysis of signalling networks’, Prog. Biophys. Mol. Bio., 2004, 86, pp. 543.
    32. 32)
      • 32. Nguyen, L.N., Kholodenko, B.N.: ‘Feedback regulation in cell signalling: lesson for cancer therapeutics’, Sem. Cell Dev. Biol., 2016, 50, pp. 8594.
    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. 17.
    34. 34)
      • 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. 24772488.
    35. 35)
      • 35. Alalem, M., Ray, A., Ray, B.K.: ‘Metformin induces degradation of mTOR protein in breast cancer cells’, Cancer Med., 2016, 5, (11), pp. 31943204.
    36. 36)
      • 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. 159168.
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