Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses

Abstract

Although p53-mediated cell-cycle arrest, senescence, and apoptosis remain critical barriers to cancer development, the emerging role of p53 in cell metabolism, oxidative responses, and ferroptotic cell death has been a topic of great interest. Nevertheless, it is unclear how p53 orchestrates its activities in multiple metabolic pathways into tumor suppressive effects. Here, we identified the SAT1 (spermidine/spermine N 1 -acetyltransferase 1) gene as a transcription target of p53. SAT1 is a rate-limiting enzyme in polyamine catabolism critically involved in the conversion of spermidine and spermine back to putrescine. Surprisingly, we found that activation of SAT1 expression induces lipid peroxidation and sensitizes cells to undergo ferroptosis upon reactive oxygen species (ROS)-induced stress, which also leads to suppression of tumor growth in xenograft tumor models. Notably, SAT1 expression is down-regulated in human tumors, and CRISPRcas9-mediated knockout of SAT1 expression partially abrogates p53-mediated ferroptosis. Moreover, SAT1 induction is correlated with the expression levels of arachidonate 15-lipoxygenase (ALOX15), and SAT1-induced ferroptosis is significantly abrogated in the presence of PD146176, a specific inhibitor of ALOX15. Thus, our findings uncover a metabolic target of p53 involved in ferroptotic cell death and provide insight into the regulation of polyamine metabolism and ferroptosis-mediated tumor suppression.SAT1 | p53 | polyamine metabolism | ferroptosis | tumor suppression

On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death

“…25,26,53,63 One such study suggested that α-TOH inhibits ferroptosis by LO inhibition. 63 The basis for this assertion was that tocotrienols were demonstrably more effective inhibitors of ferroptosis than tocopherols, and tocotrienols were predicted to bind more strongly to 15-LOX-1 than tocopherols owing to the three unsaturations in their lipophilic side chains.…”

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

“…Thus, selenium supplementation promotes ferroptosis resistance, while selenium depletion promotes ferroptosis sensitivity, presumably by modulating GPX4 abundance and activity (Cardoso et al, 2017). A number of other genes have been implicated as modulators of sensitivity to ferroptosis or markers of ferroptosis in diverse contexts: SAT1 , which lies downstream of p53 (Ou et al, 2016) is involved in polyamine metabolism; kiss of death (KOD) in Arabidopsis (Distefano et al, 2017) and FANCD2 in bone marrow stromal cells are induced during ferroptosis (Song et al, 2016); TTC35 , CS , ATP5G3 , and RPL8 are involved in diverse processes in human cancer cells and suppress erastin-induced ferroptosis upon knockdown (Dixon et al, 2012). …”

Antioxidants Maintain Cellular Redox Homeostasis by Elimination of Reactive Oxygen Species

“…SAT1 is a rate-limiting enzyme in polyamine catabolism critically involved in the conversion of spermidine and spermine back to putrescine. Surprisingly, activation of SAT1 expression induces lipid peroxidation and sensitizes cells to undergo ferroptosis upon ROS-induced stress [78]. …”