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Activating Akt1 mutations alter DNA double strand break repair and radiosensitivity

S Oeck1, K Al-Refae1, H Riffkin1

  • 1Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Virchowstrasse 173, 45122 Essen, Germany.

Scientific Reports
|February 18, 2017
PubMed

Insights

The survival kinase Akt influences radioresistance, but its role in DNA repair and cell death is unclear. Specific Akt1 mutations enhance DNA double-strand break repair and cell survival, suggesting targeted inhibition for cancer therapy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Radiation Response

Background:

  • The survival kinase Akt is implicated in radioresistance, but its precise roles in DNA damage response, DNA double-strand break (DSB) repair, and apoptosis are not well understood.
  • Existing data on Akt's contribution to cellular radiation response are often contradictory, necessitating further investigation into its specific functions.

Purpose of the Study:

  • To genetically investigate the impact of Akt1 alterations on the cellular response to radiation.
  • To clarify the relationship between Akt1 activation status, nuclear localization, and radioresistance.

Main Methods:

  • Utilized a genetic approach involving Akt1 activation mutants (Akt1-TDSD, Akt1-E17K, myrAkt1) in Tramp-C1 murine prostate cancer cells and Akt1-knockout murine embryonic fibroblasts.
  • Performed in vitro kinase assays to assess direct phosphorylation of Akt1 by DNA-PKcs.
  • Investigated the effects of pharmacological inhibition of DNA-PKcs and Akt on radiosensitivity.

Main Results:

  • Specific Akt1 mutants (Akt1-TDSD, Akt1-E17K) with nuclear access accelerated DSB repair and enhanced survival of irradiated cells.
  • The membrane-targeted myrAkt1 mutant exhibited opposite effects, impairing survival and DSB repair.
  • DNA-PKcs was found to directly phosphorylate Akt1 at S473, but not vice-versa.
  • Pharmacological inhibition of DNA-PKcs or Akt reversed radioresistance in cells expressing Akt1-E17K or Akt1-TDSD.

Conclusions:

  • Akt1-mediated radioresistance is dependent on its activation state and subcellular localization (nuclear access).
  • Targeted inhibition of DNA-PKcs or Akt can overcome Akt1-driven radioresistance.
  • These findings highlight the potential of pharmacologic strategies targeting Akt signaling for improving cancer radiotherapy outcomes.

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