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Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN(+/-) mice

Jose R Bayascas1, Nick R Leslie, Ramon Parsons

  • 1MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom. j.bayascas@dundee.ac.uk

Current Biology : CB
|October 26, 2005
PubMed

Insights

Loss of PTEN tumor suppressor function elevates cancer-promoting signals. Reducing PDK1 kinase activity in PTEN-deficient mice significantly prevents tumor development, identifying PDK1 as a key cancer target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Elevated phosphatidylinositol (3,4,5)-trisphosphate) levels are common in many cancers, driving cell proliferation and survival.
  • The tumor suppressor PTEN normally degrades phosphatidylinositol (3,4,5)-trisphosphate, and its mutation is frequent in human cancers.
  • PTEN loss leads to increased phosphatidylinositol (3,4,5)-trisphosphate, activating protein kinase B (PKB/Akt) and S6 kinase (S6K), promoting tumorigenesis.

Purpose of the Study:

  • To investigate the role of 3-phosphoinositide-dependent kinase 1 (PDK1) in tumorigenesis associated with PTEN loss.
  • To determine if PDK1 is a critical mediator of neoplasia driven by the PI3K/Akt/S6K pathway.

Main Methods:

  • Utilized heterozygous PTEN (+/-) mice, a model for various spontaneous tumors.
  • Genetically reduced PDK1 expression in PTEN (+/-) mice.
  • Observed tumor development and progression in mice with varying levels of PTEN and PDK1.

Main Results:

  • Reducing PDK1 expression in PTEN (+/-) mice markedly protected them from developing a wide spectrum of tumors.
  • This protection correlated with reduced activity of PKB/Akt and S6K signaling pathways.
  • Genetic evidence implicates PDK1 as a crucial effector in PTEN-deficient tumorigenesis.

Conclusions:

  • PDK1 is a key mediator of neoplasia resulting from PTEN loss.
  • PDK1 is a validated and promising therapeutic target for preventing cancers with elevated PKB/Akt and S6K activity.

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