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Therapeutics

Akt: a double-edged sword

Nature Reviews Cancer volume 9, pages 76–77 (2009)Cite this article

Veronique Nogueira and colleagues investigated cellular lifespan in AKT1 and AKT2 double-knockout primary mouse fibroblasts and found that these cells senesced later than wild-type cells, indicating that Akt regulates lifespan and senescence. Because reactive oxygen species (ROS) have previously been shown to regulate these processes, the authors examined the levels of ROS in the double-knockout cells and found that ROS levels were significantly lower than in wild-type cells. Akt increases the production of ROS, which sensitize Akt-expressing cells to senescence. They focused on downstream effectors of Akt, showing that Akt-induced ROS accumulation and senescence is mediated by the forkhead box O (Foxo) family of transcription factors. Akt impairs ROS scavenging by antioxidant factors, such as sestrin 3, by inhibiting Foxo-mediated transcription of these genes.

The authors also found that, despite the ability of hyperactive Akt to inhibit apoptosis that is induced by a variety of apoptotic stimuli, it could not inhibit apoptosis that is induced by ROS inducers. Furthermore, because Akt increases intracellular levels of ROS and impairs ROS scavenging, cells expressing hyperactive Akt are sensitized to ROS-induced cell death.

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References

ORIGINAL RESEARCH PAPER

  1. Nogueira, V. et al. Akt determines replicative senescence and oxidative or oncogenic premature sensescence and sensitizes cells to oxidative stress. Cancer Cell 14, 458–470 (2008)

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FURTHER READING

  1. Sabatini, D.M. mTOR and cancer: insights into a complex relationship. Nature Rev. Cancer 6, 729–734 (2006)

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Authors
  1. Meera Swami
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Swami, M. Akt: a double-edged sword. Nat Rev Cancer 9, 76–77 (2009). https://doi.org/10.1038/nrc2586

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