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Silencing p110β prevents rapid depletion of nuclear pAkt

Zhi-wei Ye1, Aram Ghalali, Johan Högberg

  • 1Institute of Environmental Medicine, Karolinska Institutet, S-17177 Stockholm, Sweden.

Biochemical and Biophysical Research Communications
|November 15, 2011
PubMed

Insights

The p110β subunit is crucial for reducing nuclear phosphorylated Akt (pAkt) levels, a process triggered by ATP or statins. This finding highlights p110β

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • The p110β subunit of class IA phosphoinositide 3-kinase (PI3K) is implicated as an oncogene in prostate cancer.
  • Extracellular ATP and statins induce a rapid depletion of nuclear phosphorylated Akt (pAkt), a process mediated by the P2X7 receptor.
  • PTEN loss is linked to prostate tumor development, and p110β plays a role in this context.

Purpose of the Study:

  • To investigate the role of the p110β subunit in the ATP- or statin-induced depletion of nuclear pAkt.
  • To determine if p110β is essential for the anti-proliferative effects of ATP, statins, or P2X7 agonists.
  • To explore the involvement of p110β in statin-induced alterations of protein interactions involving FKBP51, pAkt, and PTEN.

Main Methods:

  • Utilized p110β knockout mouse embryonic fibroblasts (MEFs) and siRNA-treated cancer cells.
  • Assessed the impact of ATP, statins, and BzATP (a selective P2X7 agonist) on nuclear pAkt levels.
  • Monitored cell growth inhibition and changes in protein binding interactions (FKBP51, pAkt, PTEN).

Main Results:

  • p110β knockout MEFs and siRNA-treated cancer cells showed no depletion of nuclear pAkt upon ATP or statin treatment.
  • ATP, statins, and BzATP inhibited cell growth, but this effect was abrogated in p110β knockout cells.
  • p110β was essential for statin-induced modifications in the binding of FKBP51, pAkt, and PTEN.

Conclusions:

  • p110β is indispensable for the ATP- and statin-mediated depletion of nuclear pAkt.
  • Nuclear pAkt plays a significant role in cancer development, and its depletion by p110β is a key mechanism.
  • Statins may exert chemopreventive effects through the p110β-dependent depletion of nuclear pAkt.

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