Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis

By V. Nogueira, Youngkyu Park, Chia-Chen Chen, Pei-Zhang Xu, Mei-Ling Chen, Ivana Tonic, T. Unterman, N. Hay. Cancer Cell, 2008

771 citations recorded by the source corpus.

Summary Akt-deficiency causes resistance to replicative senescence, oxidative stress- or 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 sestrin3 expression. 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/47ae93b1c962b3a2ea9f0dfe1857353c66cb6a7e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

Citations in the corpus

Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). (2012, background): “In addition, lactic acidosis inhibits glycolysis and favors aerobic respiration as a means of energy generation (14). ⅳ) Due to the decrease of mitochondrial OXPHOS, less reactive oxygen species (ROS) are generated, which are cytotoxic to cancer cells (34,35).”
Redox regulation of FoxO transcription factors (2015, background): “In human fibroblasts, E2F-1 enhances cellular senescence, whereas FoxOs antagonize senescence by upregulating the formation of ROS scavenging proteins [154,155].”
The Role of Sirtuins in Antioxidant and Redox Signaling (2017, background): “This raises metabolic activity in the mitochondria and inhibits FOXO transcriptional activity, resulting in greatly increased ROS levels, which sensitizes cancer cells to apoptosis induced by oxidative stimuli (35, 115).”
Regulation of cancer cell metabolism (2011, result): “Similar results have been seen with loss of PTEN, and hyperactivation of AKT1 leads to FOXO inactivation and increased oxidative stres”
Senescence and apoptosis: dueling or complementary cell fates? (2014, neutral): “Conversely, AKT deficiency confers resistance to replicative- and Ras-induced senescence and promotes apoptosis under conditions of oxidative stress [77].”
ROS Function in Redox Signaling and Oxidative Stress (2014, background): “If cancer cells do not control their ROS levels then they are susceptible to oxidative-stress-induced cell death [46,47].”
Depletion of a Putatively Druggable Class of Phosphatidylinositol Kinases Inhibits Growth of p53-Null Tumors (2013, background): “Hyperactivation of the PI3K/AKT pathway due to loss of PTEN (and INPP4B) has previously been shown to induce senescence (Chen et al., 2005; Gewinner et al., 2009; Nogueira et al., 2008), raising the possibility that activation of AKT in response to PI5P4Ka/b knockdown is responsible for the senescen”
Fasting Cycles Retard Growth of Tumors and Sensitize a Range of Cancer Cell Types to Chemotherapy (2012, background): “In both yeast and higher eukaryotes, the activation of Akt and TOR-S6K pathways promotes oxidative stress and sensitizes cells to oxidative damage, in part by in activating stress resistance transcription factors (26, 27).”