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.
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Abbreviations
- 2-DG:
-
2-deoxyglucose
- AICAR:
-
5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide
- AMPK:
-
AMP-activated protein kinase
- ER:
-
endoplasmic reticulum
- GSK3:
-
glycogen synthase 3
- HBSS:
-
Hanks buffered salt solution
- mTOR:
-
mammalian target of rapamycin
- mTORC1:
-
mTOR complex 1
- PARP:
-
poly (ADP-ribose) polymerase
- PI3K:
-
phosphoinositide-3 kinase
- PTEN:
-
phosphatase and tensin homolog
- ROS:
-
reactive oxygen species
- TSC2:
-
tuberous sclerosis protein 2
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Acknowledgements
We thank Pierre Roux for the p53−/− MEFs. We thank Mireille Cormont, Sophie Giorgetti-Peraldi, Béatrice Bailly Maitre, Jean Ehrland Ricci and Yannick Le Marchand Brustel for scientific discussion. This study was supported by The European Foundation for the Study of Diabetes (EFSD) and INCA (grant 2010–219 and 2010–214). IB-S was supported by ‘La Ligue Nationale contre le cancer’. IB-S and AP received the ‘Prix Jeune Chercheur’ of the Bettencourt foundation. BD is supported by INCA grant 2010–219. FB and J-FT are investigators of the Center National de la Recherche Scientifique (CNRS).
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Ben-Sahra, I., Dirat, B., Laurent, K. et al. Sestrin2 integrates Akt and mTOR signaling to protect cells against energetic stress-induced death. Cell Death Differ 20, 611–619 (2013). https://doi.org/10.1038/cdd.2012.157
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DOI: https://doi.org/10.1038/cdd.2012.157
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