Sestrin2 integrates Akt and mTOR signaling to protect cells against energetic stress-induced death

I. Ben-Sahra, B. Dirat, K. Laurent, A. Puissant, P. Auberger, A. Budanov, J. F. Tanti, F. Bost*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

The phosphoinositide-3 kinase/Akt (PI3K/Akt) pathway has a central role in cancer cell metabolism and proliferation. More importantly, it is one of the cardinal pro-survival pathways mediating resistance to apoptosis. The role of Akt in response to an energetic stress is presently unclear. Here, we show that Sestrin2 (Sesn2), also known as Hi95, a p53 target gene that protects cells against oxidative and genotoxic stresses, participates in the protective role of Akt in response to an energetic stress induced by 2-deoxyglucose (2-DG). Sesn2 is upregulated in response to an energetic stress such as 2-DG and metformin, and mediates the inhibition of mammalian target of rapamycin (mTOR), the major cellular regulator of energy metabolism. The increase of Sesn2 is independent of p53 but requires the anti-apoptotic pathway, PI3K/Akt. Inhibition of Akt, as well as loss of Sesn2, sensitizes cells to 2-DG-induced apoptosis. In addition, the rescue of Sesn2 partially reverses the pro-apoptotic effects of 2-DG. In conclusion, we identify Sesn2 as a new energetic stress sensor, which appears to be protective against energetic stress-induced apoptosis that integrates the pro-survival function of Akt and the negative regulation of mTOR.

Original languageEnglish (US)
Pages (from-to)611-619
Number of pages9
JournalCell Death and Differentiation
Volume20
Issue number4
DOIs
StatePublished - Apr 2013

Keywords

  • 2-deoxyglucose
  • AMPK
  • Apoptosis
  • Cell metabolism
  • Metformin
  • Sestrin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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