Bifurcation analysis of insulin regulated mTOR signalling pathway in cancer cells.

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.