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How moderate changes in Akt T-loop phosphorylation impact on tumorigenesis and insulin resistance

Stephan Wullschleger1, Kei Sakamoto, Lana Johnstone

  • 1MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

Disease Models & Mechanisms
|October 21, 2010
PubMed

Insights

Modestly reducing Akt signalling activity in mice improved insulin sensitivity and delayed tumor onset and growth. This suggests targeted Akt pathway inhibition could treat insulin resistance and cancer.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • The Akt signalling pathway is crucial for insulin response, cell proliferation, and survival.
  • Dysregulation of Akt activity is linked to insulin resistance, type 2 diabetes, and cancer.
  • Understanding the impact of modest Akt modulation is key for therapeutic development.

Purpose of the Study:

  • To investigate the effects of moderate Akt pathway modulation on insulin resistance and tumorigenesis.
  • To assess the therapeutic potential of targeting Akt signalling for metabolic and oncological conditions.

Main Methods:

  • Utilized PDK1(K465E/K465E) PH domain knock-in mice to model insulin resistance.
  • Introduced PTEN(+/-) mutations to modulate Akt activity.
  • Assessed tumour onset and growth in genetically engineered mouse models using magnetic resonance imaging.

Main Results:

  • Slightly stimulating Akt in insulin-resistant mice restored normal insulin sensitivity.
  • A ~50% reduction in Akt activity in cancer-prone mice delayed tumour onset by approximately 4 months.
  • Slower growth of B cell follicular lymphomas was observed in treated mice.

Conclusions:

  • Modest reductions in Akt activity can restore insulin sensitivity.
  • Targeting the Akt pathway with signal transduction inhibitors may offer a dual therapeutic strategy for insulin resistance and cancer.
  • Inhibitors that moderately decrease Akt activity could delay tumourigenesis and slow the growth of existing tumours.

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