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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular

A Khwaja1, P Rodriguez-Viciana, S Wennström

  • 1Imperial Cancer Research Fund, London, UK.

The EMBO Journal
|May 15, 1997
PubMed

Insights

Ras oncogenes prevent anoikis, a form of apoptosis, by activating phosphoinositide 3-OH kinase (PI 3-kinase) and protein kinase B/Akt (PKB/Akt). This pathway mediates survival signals in both normal and Ras-transformed epithelial cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Epithelial cells undergo anoikis (apoptosis) upon detachment from the extracellular matrix.
  • Oncogenic Ras proteins can inhibit anoikis, promoting cancer cell survival.
  • The specific signaling pathways involved in anoikis inhibition by Ras are not fully understood.

Purpose of the Study:

  • To elucidate the signaling mechanisms by which oncogenic Ras and extracellular matrix attachment prevent anoikis.
  • To identify the key molecular mediators of anoikis resistance in epithelial cells.

Main Methods:

  • Investigated the role of phosphoinositide 3-OH kinase (PI 3-kinase) and Raf signaling pathways.
  • Utilized constitutively active and inhibitory forms of PI 3-kinase and protein kinase B/Akt (PKB/Akt).
  • Assessed apoptosis in adherent and detached epithelial cells, including Ras-transformed cells.

Main Results:

  • PI 3-kinase, acting through PKB/Akt, mediates survival against anoikis induced by matrix detachment.
  • Constitutive activation of PI 3-kinase or PKB/Akt prevents anoikis.
  • Inhibition of PI 3-kinase blocks Ras-mediated anoikis protection, while PKB/Akt inhibition does not.
  • PI 3-kinase and PKB/Akt activity are elevated in Ras-transformed cells, even in suspension.

Conclusions:

  • PI 3-kinase and PKB/Akt are key mediators of anoikis resistance in Ras-transformed cells.
  • This pathway is also crucial for matrix-induced survival of normal epithelial cells.
  • Targeting PI 3-kinase/PKB/Akt may offer therapeutic strategies for cancers exhibiting anoikis resistance.

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