INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France.
Cell Death Differ. 2013 Apr;20(4):611-9. doi: 10.1038/cdd.2012.157. Epub 2012 Dec 14.
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.
磷酸肌醇 3 激酶/蛋白激酶 B（PI3K/Akt）通路在癌细胞代谢和增殖中起着核心作用。更重要的是，它是介导细胞凋亡抵抗的主要生存途径之一。Akt 在应对能量应激中的作用目前尚不清楚。在这里，我们表明 Sestrin2（Sesn2），也称为 Hi95，一种 p53 靶基因，可保护细胞免受氧化和遗传毒性应激，参与 Akt 在应对 2-脱氧葡萄糖（2-DG）诱导的能量应激中的保护作用。Sesn2 响应能量应激（如 2-DG 和二甲双胍）而上调，并介导哺乳动物雷帕霉素靶蛋白（mTOR）的抑制，mTOR 是细胞能量代谢的主要调节剂。Sesn2 的增加独立于 p53，但需要抗凋亡途径 PI3K/Akt。抑制 Akt 以及丧失 Sesn2 可使细胞对 2-DG 诱导的细胞凋亡敏感。此外，Sesn2 的挽救部分逆转了 2-DG 的促凋亡作用。总之，我们将 Sesn2 鉴定为一种新的能量应激传感器，它似乎可以防止能量应激诱导的细胞凋亡，整合了 Akt 的生存促进功能和 mTOR 的负调控。
