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Metastasis and AKT activation

Meng Qiao1, Shijie Sheng, Arthur B Pardee

  • 1Dana-Farber Cancer Institute, Boston, Massachusetts, USA. meng_qiao@dfci.harvard.edu

Cell Cycle (Georgetown, Tex.)
|September 27, 2008
PubMed

Insights

The activated AKT pathway drives cancer metastasis by promoting cell escape and growth. Understanding AKT

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Metastasis is a critical factor in 90% of cancer-related deaths, necessitating research into its molecular mechanisms for improved detection and treatment.
  • The activated AKT kinase plays a crucial role in multiple metastatic processes, including cellular detachment, proliferation, apoptosis evasion, and angiogenesis.
  • Activation of AKT, often through phosphorylation at Ser-473, initiates a cascade of events critical for the development of metastatic properties.

Purpose of the Study:

  • To investigate the molecular connections between AKT activation and the metastatic cascade.
  • To elucidate the mechanisms by which AKT becomes hyperactivated in metastatic cancer cells.
  • To identify potential therapeutic targets within the AKT signaling pathway.

Main Methods:

  • Analysis of the AKT signaling pathway and its downstream targets.
  • Investigation of factors influencing AKT activation, including PI3K, TORC2, PHLPP, and PTEN.
  • Examination of the role of SNAIL and E-cadherin in AKT-mediated metastasis.

Main Results:

  • Activated AKT phosphorylates GSK-3beta, leading to its degradation and increased stability of the transcription factor SNAIL.
  • Decreased E-cadherin transcription, resulting from SNAIL stabilization, reduces cell-cell adhesion and facilitates cellular detachment.
  • Potential mechanisms for AKT hyperactivation include increased PI3K or TORC2 activity, or decreased PHLPP phosphatase activity.
  • A positive feedback loop involving decreased E-cadherin, reduced PTEN, and increased PIP3 further enhances AKT activation and promotes metastasis.

Conclusions:

  • The activated AKT pathway is a central regulator of cancer metastasis through its effects on cell adhesion, proliferation, and survival.
  • Dysregulation of key components in the PI3K/AKT pathway, such as PI3K, TORC2, PHLPP, and PTEN, contributes to AKT hyperactivation in metastatic cells.
  • Targeting the AKT signaling pathway and its downstream effectors represents a promising strategy for the development of novel anti-metastatic therapies.

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