Akt regulation of glycolysis mediates bioenergetic stability in epithelial cells

Albeck, John G.; Hung, Yin P.; Teragawa, Carolyn K.; Pargett, Michael; Gillies, Taryn E.; Minguet, Marta; Distor, Kevin; Rocha-Gregg, Briana L; Kosaisawe, Nont; Brugge, Joan S.; Yellen, Gary

doi:10.1101/126771

Cited by 10 publications

(14 citation statements)

References 60 publications

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“…We were therefore interested if a distinct metabolic profile of the leukemic cells would be associated with a different prerequisite activity of the signaling pathways. Indeed, we found a profound difference in p-AKT and c-MYC, the regulators of glycolysis [21,22], between T-and B-ALL cells and decreased level of p-GSK3b in B-ALL cell lines. In the case of the AML cell lines, the proteins S6 and p-S6 were more expressed than in ALL cells.…”

Section: Discussionmentioning

confidence: 75%

Metabolic profile of leukemia cells influences treatment efficacy of L-asparaginase

et al. 2020

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Background: Effectiveness of L-asparaginase administration in acute lymphoblastic leukemia treatment is mirrored in the overall outcome of patients. Generally, leukemia patients differ in their sensitivity to L-asparaginase; however, the mechanism underlying their inter-individual differences is still not fully understood. We have previously shown that L-asparaginase rewires the biosynthetic and bioenergetic pathways of leukemia cells to activate both antileukemic and pro-survival processes. Herein, we investigated the relationship between the metabolic profile of leukemia cells and their sensitivity to currently used cytostatic drugs. Methods: Altogether, 19 leukemia cell lines, primary leukemia cells from 26 patients and 2 healthy controls were used. Glycolytic function and mitochondrial respiration were measured using Seahorse Bioanalyzer. Sensitivity to cytostatics was measured using MTS assay and/or absolute count and flow cytometry. Mitochondrial membrane potential was determined as TMRE fluorescence. Results: Using cell lines and primary patient samples we characterized the basal metabolic state of cells derived from different leukemia subtypes and assessed their sensitivity to cytostatic drugs. We found that leukemia cells cluster into distinct groups according to their metabolic profile. Lymphoid leukemia cell lines and patients sensitive to L-asparaginase clustered into the low glycolytic cluster. While lymphoid leukemia cells with lower sensitivity to L-asparaginase together with resistant normal mononuclear blood cells gathered into the high glycolytic cluster. Furthermore, we observed a correlation of specific metabolic parameters with the sensitivity to L-asparaginase. Greater ATP-linked respiration and lower basal mitochondrial membrane potential in cells significantly correlated with higher sensitivity to L-asparaginase. No such correlation was found in the other cytostatic drugs tested by us.

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Section: Discussionmentioning

confidence: 75%

Metabolic profile of leukemia cells influences treatment efficacy of L-asparaginase

et al. 2020

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“…This inhibition might result from the glutamate-induced decrease in [Mg 2+ ] i demonstrated in this study ( Figure 2 and Figure 3 ). The fact that the Akt/mTOR signal is also involved in regulation of both cellular ATP synthesis and also apoptotic signals [ 35 , 46 , 47 ] would explain why maintaining a high [Mg 2+ ] i prevent neuronal cell death. In this study, we showed that inhibition of mTOR abolished the attenuation of glutamate excitotoxicity by inhibiting Mg 2+ extrusion ( Figure 6 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Mg2+ Extrusion Attenuates Glutamate Excitotoxicity in Cultured Rat Hippocampal Neurons

et al. 2020

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Magnesium plays important roles in the nervous system. An increase in the Mg2+ concentration in cerebrospinal fluid enhances neural functions, while Mg2+ deficiency is implicated in neuronal diseases in the central nervous system. We have previously demonstrated that high concentrations of glutamate induce excitotoxicity and elicit a transient increase in the intracellular concentration of Mg2+ due to the release of Mg2+ from mitochondria, followed by a decrease to below steady-state levels. Since Mg2+ deficiency is involved in neuronal diseases, this decrease presumably affects neuronal survival under excitotoxic conditions. However, the mechanism of the Mg2+ decrease and its effect on the excitotoxicity process have not been elucidated. In this study, we demonstrated that inhibitors of Mg2+ extrusion, quinidine and amiloride, attenuated glutamate excitotoxicity in cultured rat hippocampal neurons. A toxic concentration of glutamate induced both Mg2+ release from mitochondria and Mg2+ extrusion from cytosol, and both quinidine and amiloride suppressed only the extrusion. This resulted in the maintenance of a higher Mg2+ concentration in the cytosol than under steady-state conditions during the ten-minute exposure to glutamate. These inhibitors also attenuated the glutamate-induced depression of cellular energy metabolism. Our data indicate the importance of Mg2+ regulation in neuronal survival under excitotoxicity.

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“…However, these interactions have not been yet observed in matrix-deprivation conditions. Such context-specific differences may allow for other dynamics for AMPK and Akt, such as oscillations seen in MCF10A cells upon inhibition of glycolysis and mitochondrial ATPase [65]. Intriguingly, AMPK can form double negative feedback loops with other molecules such as mTORC1 [66], which is involved in a similar feedback loop with ULK1 [67].…”

Section: Discussionmentioning

confidence: 99%

Multistability and consequent phenotypic plasticity in AMPK-Akt double negative feedback loop in cancer cells

Chedere

Hari

Kumar

et al. 2020

Preprint

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Adaptation and survival of cancer cells to various stress and growth factor conditions is crucial for successful metastasis. A double-negative feedback loop between two serine/threonine kinases AMPK and Akt can regulate the adaptation of breast cancer cells to matrix-deprivation stress. This feedback loop can generate majorly two phenotypes or cell states: matrix detachment-triggered pAMPKhigh/ pAktlow state, and matrix (re)attachment-triggered pAkthigh/ pAMPKlow state. However, whether these two cell states can exhibit phenotypic plasticity and heterogeneity in a given cell population, i.e., whether they can co-exist and undergo spontaneous switching to generate the other subpopulation, remains unclear. Here, we develop a mechanism-based mathematical model that captures the set of experimentally reported interactions among AMPK and Akt. Our simulations suggest that the AMPK-Akt feedback loop can give rise to two co-existing phenotypes (pAkthigh/ pAMPKlow and pAMPKhigh/pAktlow) in specific parameter regimes. Next, to test the model predictions, we segregated these two subpopulations in MDA-MB-231 cells and observed that each of them was capable of switching to another in adherent conditions. Finally, the predicted trends are supported by clinical data analysis of TCGA breast cancer and pan-cancer cohorts that revealed negatively correlated pAMPK and pAkt protein levels. Overall, our integrated computational-experimental approach unravels that AMPK-Akt feedback loop can generate multistability and drive phenotypic switching and heterogeneity in a cancer cell population.

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Akt regulation of glycolysis mediates bioenergetic stability in epithelial cells

Cited by 10 publications

References 60 publications

Metabolic profile of leukemia cells influences treatment efficacy of L-asparaginase

Metabolic profile of leukemia cells influences treatment efficacy of L-asparaginase

Inhibition of Mg2+ Extrusion Attenuates Glutamate Excitotoxicity in Cultured Rat Hippocampal Neurons

Multistability and consequent phenotypic plasticity in AMPK-Akt double negative feedback loop in cancer cells

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