The Role of the P53-P21 Pathway in Metabolic Stress-induced Ferroptosis

Download or read book The Role of the P53-P21 Pathway in Metabolic Stress-induced Ferroptosis written by Amy N. Tarangelo and published by . This book was released on 2020 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Ferroptosis is a form of iron-dependent, non-apoptotic cell death that occurs due to the collapse of the glutathione peroxidase antioxidant system and the lethal accumulation of lipid peroxides. Selectively inducing ferroptosis in cancer cells represents a promising therapeutic strategy. However, it remains unclear how canonical tumor suppressors and oncogenes influence cell susceptibility to ferroptosis. The p53 tumor suppressor gene is the most commonly mutated gene in human cancers and serves as a master regulator of cell stress responses, metabolic adaptation, DNA damage repair, and cell death. Using a time-lapse microscopy system to study cell death kinetics over time, I found that activation of wild-type p53 suppresses the onset of ferroptosis in human cancer cells, and that deletion of p53 results in heightened ferroptosis sensitivity. The transcriptional activity of p53 is required for this function, in part through transactivation of CDKN1A (encoding p21). Activation of the p53-p21 pathway suppresses the accumulation of lipid peroxides and promotes the conservation of glutathione, an essential antioxidant required for the reduction of lipid peroxides. p53-p21 pathway activation results in decreased expression of the enzyme ribonucleotide reductase (RNR), which uses glutathione as a cofactor in the reduction of ribonucleotides to deoxyribonucleotides. Genetic and chemical inhibition of RNR is sufficient to suppress ferroptosis and conserve glutathione similar to chemical activators of the p53-p21 pathway. These results suggest that the ability of the p53-p21 pathway to downregulate RNR may allow cells to conserve glutathione and direct it towards the management of lipid peroxides during ferroptosis. This work supports the known role for wild-type p53 in regulating cell survival under conditions of metabolic stress and identifies nucleotide metabolism as a new regulator of ferroptosis in cancer cells. These findings have important implications for the development of ferroptosis-based therapies for human disease.