title: Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Veronique
authors.initials: V
authors.lastname: Nogueira
authors.forename: Youngkyu
authors.initials: Y
authors.lastname: Park
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Chen
authors.forename: Pei-Zhang
authors.initials: PZ
authors.lastname: Xu
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Chen
authors.forename: Ivana
authors.initials: I
authors.lastname: Tonic
authors.forename: Terry
authors.initials: T
authors.lastname: Unterman
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
mesh_terms: 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
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D020123:Sirolimus