Mosca2012 - Central Carbon Metabolism Regulated by AKT

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Mosca2012 - Central Carbon Metabolism Regulated by AKT

The role of the PI3K/Akt/PKB signalling pathway in oncogenesis has been extensively investigated and altered expression or mutations of many components of this pathway have been implicated in human cancers. Indeed, expression of constitutively active forms of Akt/PKB can prevent cell death upon growth factor withdrawal. PI3K/Akt/mTOR-mediated survival relies on a profound metabolic adaptation, including aerobic glycolysis. Here, the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis has been modelled, considering two states - high and low PI3K/Akt/mTOR activity. The high PI3K/Akt/mTOR activity represents cancer cell line where PI3K/Akt/mTOR promotes a high rate of glucose metabolism (condition H) and the low PI3K/Akt/mTOR activity is characterised by a lower glycolytic rate due to a reduced PI3K/Akt/mTOR signal (condition L). This model corresponds to the high PI3K/Akt/mTOR signal (condition H).

This model is described in the article:

Mosca E, Alfieri R, Maj C, Bevilacqua A, Canti G, Milanesi L.
Frontiers in Systems Biology. 2012 Oct 13

Abstract:

Signal transduction pathways and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB), also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two activities shown by both normal and cancer proliferating cells. Not surprisingly considering its relevance for cellular metabolism, Akt/PKB is often found hyperactive in cancer cells. In the last decade, many efforts have been made to improve the understanding of the control of glucose metabolism and the identification of a therapeutic window between proliferating cancer cells and proliferating normal cells. In this context, we have modelled the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis. We used a computational model in order to compare two metabolic states generated by the specific variation of the metabolic fluxes regulated by the activity of the PI3K/Akt/mTOR pathway. One of the two states represented the metabolism of a growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis, while the other state represented the same metabolic network with a reduced glycolytic rate and a higher mitochondrial pyruvate metabolism, as reported in literature in relation to the activity of the PI3K/Akt/mTOR. Some steps that link glycolysis and pentose phosphate pathway revealed their importance for controlling the dynamics of cancer glucose metabolism.

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Format
SBML (L2V4)
Related Publication
  • Computational modeling of the metabolic States regulated by the kinase akt.
  • Mosca E, Alfieri R, Maj C, Bevilacqua A, Canti G, Milanesi L
  • Frontiers in physiology , 0/ 2012 , Volume 3 , pages: 418
  • Institute for Biomedical Technologies, Consiglio Nazionale delle Ricerche Segrate Milano, Italy.
  • Signal transduction and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB), also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two activities shown by both normal and cancer proliferating cells. Not surprisingly considering its relevance for cellular metabolism, Akt/PKB is often found hyperactive in cancer cells. In the last decade, many efforts have been made to improve the understanding of the control of glucose metabolism and the identification of a therapeutic window between proliferating cancer cells and proliferating normal cells. In this context, we have modeled the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production, and nucleotide biosynthesis. We used a computational model to compare two metabolic states generated by two different levels of signaling through the PI3K/Akt/mTOR pathway: one of the two states represents the metabolism of a growing cancer cell characterized by aerobic glycolysis and cellular biosynthesis, while the other state represents the same metabolic network with a reduced glycolytic rate and a higher mitochondrial pyruvate metabolism. Biochemical reactions that link glycolysis and pentose phosphate pathway revealed their importance for controlling the dynamics of cancer glucose metabolism.
Contributors
Ettore Mosca

Metadata information

is
BioModels Database MODEL1210150000
BioModels Database BIOMD0000000426
isDescribedBy
PubMed 23181020
isVersionOf
hasTaxon
Brenda Tissue Ontology HeLa cell
Taxonomy Homo sapiens
hasProperty
Human Disease Ontology cancer
Curation status
Curated
  • Model originally submitted by : Ettore Mosca
  • Submitted: 15-Oct-2012 10:07:51
  • Last Modified: 09-Oct-2014 18:31:01
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 09-Oct-2014 18:31:01
    • Submitted by: Ettore Mosca
    • With comment: Current version of Mosca2012 - Central Carbon Metabolism Regulated by AKT
  • Version: 1 public model Download this version
    • Submitted on: 15-Oct-2012 10:07:51
    • Submitted by: Ettore Mosca
    • With comment: Original import of Central Carbon Metabolism Regulated by AKT
Curator's comment:
(added: 14 Nov 2012, 16:09:15, updated: 14 Nov 2012, 16:09:15)
The model compares two metabolic states generated by the specific variation of the fluxes regulated by the activity of the PI3K/Akt/mTOR pathway. One state represents the metabolism of a growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis (condition H), while the other (condition L) represented the same metabolic network with a reduced glycolytic rate, a reduced lactic acid production, but a higher mitochondrial pyruvate metabolism, in relation to a lower activity of PI3K/Akt/mTOR. Here, the model parameters corresponds to condition H (high PI3K/Akt/mTOR activity) and the table reproducing the corresponding metabolic fluxes (reported in the Appendix of the paper) has been obtained using Copasi v4.8 (Build 35).