Abstract
BackgroundNutrient acquisition and metabolism pathways are altered in cancer cells to meet bioenergetic and biosynthetic demands. A major regulator of cellular metabolism and energy homeostasis, in normal and cancer cells, is AMP-activated protein kinase (AMPK). AMPK influences cell growth via its modulation of the mechanistic target of Rapamycin (mTOR) pathway, specifically, by inhibiting mTOR complex mTORC1, which facilitates cell proliferation, and by activating mTORC2 and cell survival. Given its conflicting roles, the effects of AMPK activation in cancer can be counter intuitive. Prior to the establishment of cancer, AMPK acts as a tumor suppressor. However, following the onset of cancer, AMPK has been shown to either suppress or promote cancer, depending on cell type or state.MethodsTo unravel the controversial roles of AMPK in cancer, we developed a computational model to simulate the effects of pharmacological maneuvers that target key metabolic signalling nodes, with a specific focus on AMPK, mTORC, and their modulators. Specifically, we constructed an ordinary differential equation-based mechanistic model of AMPK-mTORC signaling, and parametrized the model based on existing experimental data.ResultsModel simulations were conducted to yield the following predictions: (i) increasing AMPK activity has opposite effects on mTORC depending on the nutrient availability; (ii) indirect inhibition of AMPK activity through inhibition of sirtuin 1 (SIRT1) only has an effect on mTORC activity under conditions of low nutrient availability; (iii) the balance between cell proliferation and survival exhibits an intricate dependence on DEP domain-containing mTOR-interacting protein (DEPTOR) abundance and AMPK activity; (iv) simultaneous direct inhibition of mTORC2 and activation of AMPK is a potential strategy for suppressing both cell survival and proliferation.ConclusionsTaken together, model simulations clarify the competing effects and the roles of key metabolic signalling pathways in tumorigenesis, which may yield insights on innovative therapeutic strategies.
Highlights
Nutrient acquisition and metabolism pathways are altered in cancer cells to meet bioenergetic and biosynthetic demands
We developed a computational model to simulate the effects of pharmacological maneuvers that target key metabolic signalling nodes, with a specific focus on AMPK, DEP domain-containing mTORinteracting protein (DEPTOR), and mTORC
At V_IR = 0.1, the decrease in activation of AMPK that follows sirtuin 1 (SIRT1) inhibition enhances Mechanistic target of rapamycin 1 (mTORC1) activation by 30% and reduces mTORC2 activation by 71% (Figs. 5A2 and A3). These effects are substantially attenuated at lower nutritional levels, with only 3 and 4% changes in mTORC1 and mTORC2 activation levels, respectively, at V_IR = 0.005 (Figs. 5B2 and B3), and with those effects becoming negligible at V_IR = 0.002687 (Figs. 5C2 and C3). These results suggest that SIRT1 inhibition may promote cell proliferation and limit survival, but that effect may be insignificant under severe nutrient deprivation
Summary
Nutrient acquisition and metabolism pathways are altered in cancer cells to meet bioenergetic and biosynthetic demands. A major regulator of cellular metabolism and energy homeostasis, in normal and cancer cells, is AMP-activated protein kinase (AMPK). AMPK influences cell growth via its modulation of the mechanistic target of Rapamycin (mTOR) pathway, by inhibiting mTOR complex mTORC1, which facilitates cell proliferation, and by activating mTORC2 and cell survival. MTOR is estimated to be hyperactivated in over 70% of cancers [4] and its hyperactivation leads to tumor growth metastasis and angiogenesis [5] This has stimulated interest in targeting mTORC1 for cancer therapy. The metabolic plasticity of cancer cells allows them to trigger mTOR-independent mechanisms to compensate for the inhibited mTOR activity, thereby allowing the cells to acquire sufficient nutrients for growth and proliferation. There is an urgent need to improve therapeutic strategies to maximize their benefits [11]
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