Abstract
The PI3K/AKT signaling pathway plays a role in most cellular functions linked to cancer progression, including cell growth, proliferation, cell survival, tissue invasion and angiogenesis. It is generally recognized that hyperactive PI3K/AKT1 are oncogenic due to their boost to cell survival, cell cycle entry and growth-promoting metabolism. That said, the dynamics of PI3K and AKT1 during cell cycle progression are highly nonlinear. In addition to negative feedback that curtails their activity, protein expression of PI3K subunits has been shown to oscillate in dividing cells. The low-PI3K/low-AKT1 phase of these oscillations is required for cytokinesis, indicating that oncogenic PI3K may directly contribute to genome duplication. To explore this, we construct a Boolean model of growth factor signaling that can reproduce PI3K oscillations and link them to cell cycle progression and apoptosis. The resulting modular model reproduces hyperactive PI3K-driven cytokinesis failure and genome duplication and predicts the molecular drivers responsible for these failures by linking hyperactive PI3K to mis-regulation of Polo-like kinase 1 (Plk1) expression late in G2. To do this, our model captures the role of Plk1 in cell cycle progression and accurately reproduces multiple effects of its loss: G2 arrest, mitotic catastrophe, chromosome mis-segregation / aneuploidy due to premature anaphase, and cytokinesis failure leading to genome duplication, depending on the timing of Plk1 inhibition along the cell cycle. Finally, we offer testable predictions on the molecular drivers of PI3K oscillations, the timing of these oscillations with respect to division, and the role of altered Plk1 and FoxO activity in genome-level defects caused by hyperactive PI3K. Our model is an important starting point for the predictive modeling of cell fate decisions that include AKT1-driven senescence, as well as the non-intuitive effects of drugs that interfere with mitosis.
Highlights
Mammalian cells require extracellular growth signals to divide and specific survival signals to avoid programmed cell death [1]
Our model reproduces a non-intuitive oscillation in a key cell division pathway (PI3K/AKT1), along with the cell-cycle altering effect of its oncogenic activation
We incorporate the role of Polo-like kinase 1 and model mitotic failure when polo-like kinase 1 (Plk1) is blocked
Summary
Mammalian cells require extracellular growth signals to divide and specific survival signals to avoid programmed cell death (apoptosis) [1]. Approaches that couple computational modeling with experimental validation have made impressive strides in deciphering the networks in charge of cell cycle progression [9,10,11] and apoptosis [12,13,14,15], as well as the mechanisms of cell cycle arrest in response to stressors such as DNA damage [16,17,18,19,20] Building on these efforts, our collective focus is increasingly shifting from models that describe individual functions towards ones that successfully integrate several aspects of cellular behavior [21,22,23,24,25,26,27,28]. Our model can reproduce non-intuitive phenotypic effects of oncogenic PI3K [29], and offer testable predictions about the molecular mechanism responsible for them
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