Akt Determines Replicative Senescence and Oxidative or Oncogenic Premature Senescence and Sensitizes Cells to Oxidative Apoptosis

被引:653
作者
Nogueira, Veronique [1 ]
Park, Youngkyu [1 ]
Chen, Chia-Chen [1 ]
Xu, Pei-Zhang [1 ]
Chen, Mei-Ling [1 ]
Tonic, Ivana [1 ]
Unterman, Terry [2 ,3 ]
Hay, Nissim [1 ]
机构
[1] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA
[2] Univ Illinois, Dept Med, Chicago, IL 60607 USA
[3] Jesse Brown VA Med Ctr, Chicago, IL 60612 USA
关键词
D O I
10.1016/j.ccr.2008.11.003
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Akt deficiency causes resistance to replicative senescence, to oxidative stress- and oncogenic Ras-induced premature senescence, and to reactive oxygen species (ROS)-mediated apoptosis. Akt activation induces premature senescence and sensitizes cells to ROS-mediated apoptosis by increasing intracellular ROS through increased oxygen consumption and by inhibiting the expression of ROS scavengers downstream of FoxO, particularly sestrin 3. This uncovers an Achilles' heel of Akt, since in contrast to its ability to inhibit apoptosis induced by multiple apoptotic stimuli, Akt could not inhibit ROS-mediated apoptosis. Furthermore, treatment with rapamycin that led to further Akt activation and resistance to etoposide hypersensitized cancer cells to ROS-mediated apoptosis. Given that rapamycin alone is mainly cytostatic, this constitutes a strategy for cancer therapy that selectively eradicates cancer cells via Akt activation.
引用
收藏
页码:458 / 470
页数:13
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