Pharmacologic inhibition of MEK and PI-3K converges on the mTOR/S6 pathway to decelerate cellular senescence
Pharmacologic inhibition of MEK and PI-3K converges on the mTOR/S6 pathway to decelerate cellular senescence
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DOI：
10.4161/cc.8.12.8809
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发表时间：
2009-06-15
期刊：
影响因子：
4.3
通讯作者：
Blagosklonny, Mikhail V.
中科院分区：
文献类型：
--
作者：
Demidenko, Zoya N.;Shtutman, Michael;Blagosklonny, Mikhail V.
雷帕霉素对mTOR的抑制可防止细胞衰老。在这里，我们研究了MEK和PI-3 K对细胞衰老的影响。与LY 294002（PI-3 K抑制剂）不同，U 0126和PD 98059（MEK抑制剂）均未显著降低衰老人成纤维细胞和纤维肉瘤细胞中的β-Gal染色。然而，使用灵敏的功能性方法，我们确定不仅LY 294002而且U 0126防止与细胞衰老相关的增殖潜力的不可逆丧失。在阻断S6磷酸化的浓度下，雷帕霉素、U 0126和LY 294002同样阻止衰老。此外，雷帕霉素与U 0126或LY 294002组合没有累加效应。总之，这表明（a）需要PI-3 K和MEK的同时活化以确保细胞衰老，并且（B）U 0126和LY 294002通过雷帕霉素敏感性途径抑制衰老。
Inhibition of mTOR by rapamycin prevents cellular senescence. Here we investigated the effects of MEK and PI-3K on cellular senescence. Unlike LY294002 (PI-3K inhibitor), both U0126 and PD98059 (MEK inhibitors) did not significantly decrease beta-Gal staining in aging human fibroblasts and fibrosarcoma cells. However, using a sensitive, functional method, we identified that not only LY294002 but also U0126 prevented irreversible loss of proliferative potential associated with cellular senescence. At concentrations that blocked S6 phosphorylation, rapamycin, U0126 and LY294002 equally prevented senescence. Furthermore, there was no additive effect by combining of rapamycin with either U0126 or LY294002. Taken together this suggests that (a) simultaneous activation of PI-3K and MEK is required to ensure cellular senescence and (b) U0126 and LY294002 suppress senescence via the rapamycin-sensitive pathway.