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Distinct roles of AKT isoforms in regulating β1-integrin activity, migration, and invasion in prostate cancer

Reetta Virtakoivu1, Teijo Pellinen, Juha K Rantala

  • 1VTT Medical Biotechnology, Turku FIN-20520, Finland.

Molecular Biology of the Cell
|July 20, 2012
PubMed

Insights

In prostate cancer cells, AKT1 and AKT2 kinases inhibit migration and invasion. Silencing these AKT kinases activates integrins, promoting cell movement and invasion through distinct molecular pathways.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • AKT1 and AKT2 kinases exhibit opposing roles in breast cancer cell migration and invasion.
  • Integrin activity is crucial for cell adhesion, migration, and invasion in various cancers.

Purpose of the Study:

  • To investigate the role of AKT isoforms (AKT1, AKT2, AKT3) in regulating cell migration and invasion in prostate cancer.
  • To elucidate the molecular mechanisms by which AKT kinases influence integrin activity and cell motility in prostate cancer.

Main Methods:

  • RNA interference (RNAi) screen to identify inhibitors of integrin activity.
  • Validation experiments using gene silencing of AKT isoforms in PC3 prostate cancer cells.
  • Analysis of cell surface β1-integrin activation, cell adhesion, migration, invasion, and focal adhesion size.
  • Investigation of downstream signaling pathways, including receptor tyrosine kinases (EGFR, MET) and microRNA-200 (miR-200) family.

Main Results:

  • Unlike in breast cancer, both AKT1 and AKT2 act as negative regulators of migration and invasion in PC3 prostate cancer cells.
  • Down-regulation of AKT1 and AKT2, but not AKT3, led to β1-integrin activation, enhanced cell adhesion, migration, and invasion, and increased focal adhesion size.
  • Silencing AKT1 reduced feedback suppression of receptor tyrosine kinases (EGFR, MET), while silencing AKT2 induced up-regulation of the miR-200 family, which was sufficient to promote integrin activity and migration.

Conclusions:

  • Both AKT1 and AKT2 play inhibitory roles in prostate cancer cell migration and invasion.
  • The mechanisms by which AKT1 and AKT2 regulate integrin activity are distinct and cell type-specific.
  • These findings highlight the complex and context-dependent functions of AKT kinases in cancer cell motility.

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