title: Sestrin2 integrates Akt and mTOR signaling to protect cells against energetic stress-induced death.
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.
authors.affiliation: INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France.
authors.forename: I
authors.initials: I
authors.lastname: Ben-Sahra
authors.forename: B
authors.initials: B
authors.lastname: Dirat
authors.forename: K
authors.initials: K
authors.lastname: Laurent
authors.forename: A
authors.initials: A
authors.lastname: Puissant
authors.forename: P
authors.initials: P
authors.lastname: Auberger
authors.forename: A
authors.initials: A
authors.lastname: Budanov
authors.forename: J-F
authors.initials: JF
authors.lastname: Tanti
authors.forename: F
authors.initials: F
authors.lastname: Bost
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003847:Deoxyglucose / Q000633:toxicity*; D006801:Humans; D008687:Metformin / Q000633:toxicity; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D000084622:Sestrins
chemical_list: D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate; D020169:Caspases; D003847:Deoxyglucose; D008687:Metformin; D009687:Nuclear Proteins; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C465398:SESN2 protein, human; D000084622:Sestrins