No abstract

Cancer metabolism is rewired to support cell survival in response to intrinsic and environmental stressors. Identification of strategies to target these adaptions is an area of active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway in pancreatic cancer used to maintain redox balance. Here, we sought to identify metabolic dependencies following GOT1 inhibition to exploit this feature of pancreatic cancer and to provide additional insight into regulation of redox metabolism. Using pharmacological methods, we identify cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. We demonstrate that targeting any of these pathways triggers ferroptosis, an oxidative, iron-dependent form of cell death, in GOT1 knockdown cells. Mechanistically, we reveal that GOT1 inhibition represses mitochondrial metabolism and promotes a catabolic state. Consequently, we find that this enhances labile iron availability through autophagy, which potentiates the activity of ferroptotic stimuli. Overall, our study identifies a biochemical connection between GOT1, iron regulation, and ferroptosis.

Aging is a multifactorial phenotype characterized by physiological changes with multifaceted effects or alterations causing gradual functional decline in a living organism (López-Otín et al., 2013). These age-associated alterations are also risk factors for various complex diseases such as cancer, diabetes, cardiovascular, and neurodegenerative diseases (López-Otín et al., 2013). Given its complex nature, the biology of aging has not been completely elucidated yet (Partridge, 2010). A number of genes and proteins in diverse biologic pathways have been implicated in influencing aging and longevity (Johnson et al., 1999). Some of the mechanisms that have

These results suggest that both of the interventions appear to be superior to usual care for the reduction of anxiety symptoms.