Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis.
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.
Nogueira
Veronique
V
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
Park
Youngkyu
Y
Chen
Chia-Chen
CC
Xu
Pei-Zhang
PZ
Chen
Mei-Ling
ML
Tonic
Ivana
I
Unterman
Terry
T
Hay
Nissim
N
D000818:Animals; D017209:Apoptosis; D016922:Cellular Senescence; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism; D018384:Oxidative Stress; D010101:Oxygen Consumption; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D020123:Sirolimus