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A novel activation-induced suicidal degradation mechanism for Akt by selenium

Ji-Hyun Lee1, Sun Hye Shin, Seongman Kang

  • 1Laboratory of Modulation of Radiobiological Responses, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.

International Journal of Molecular Medicine
|December 22, 2007
PubMed

Insights

Selenium destabilizes Akt, enhancing its enzyme activity and leading to degradation. This novel mechanism, dependent on PTEN, may explain selenium

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Selenium is linked to anti-cancer properties through Akt modulation.
  • The precise molecular mechanisms of selenium's effect on Akt are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanisms by which selenium affects Akt stability and activity.
  • To explore the role of PTEN in selenium-induced Akt modulation.

Main Methods:

  • Examined the effect of selenium on Akt stability and activity.
  • Utilized Akt mutants (T308A, S473A) and inhibited/depleted upstream kinases.
  • Investigated the requirement of PTEN for Akt destabilization in prostate cancer cells.

Main Results:

  • Selenium treatment induced Akt destabilization, which was coupled with enzyme activation.
  • Akt degradation was blocked by mutations at T308 and S473, or by inhibiting/depleting upstream kinases.
  • PTEN was essential for Akt destabilization; its absence prevented degradation even with Akt activation.
  • Restoration of PTEN in PTEN-null cells enabled Akt degradation upon selenium treatment.

Conclusions:

  • Selenium negatively regulates Akt signaling by destabilizing the Akt protein.
  • This 'activation-induced suicidal degradation' mechanism of Akt, dependent on PTEN, may underlie selenium's anti-cancer effects.
  • This pathway offers a potential paradigm for selenium's role in cancer prevention and therapy.

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