| In the recent few years, there have been numerous studies describing newly discovered cell death programs and the metabolic regulation of these cell death processes is poorly understood. Here we investigate two different cell death forms, ferroptosis and entosis, to examine how these death mechanisms are affected by conditions of metabolic stress. We have found that amino acid starvation can lead to ferroptosis of cells that have been treated with ultrasmall particles through depletion of cellular glutathione levels. This suggests that these ultrasmall silica nanoparticles, under nutrient-deprived conditions, can be utilized as inducers of ferroptosis. We have found that in vivo xenograft growth, which is accompanied by nutrient deprivation, was also inhibited with intravenous injections of these nanoparticles, suggesting the potential utilization of these particles as therapeutic agents to induce ferroptosis. We have also found that the death of live engulfed cells can be regulated by amino acids and mTOR activity. We find that amino acid withdrawal or mTOR inhibition induces apoptosis of engulfed cells and also disrupts entotic cell death that is associated with the lipidation of LC3 to entotic vacuoles. Cells ingested by two other live cell engulfment programs, homotypic cell cannibalism (HoCC) and anti-CD47 antibody-mediated phagocytosis, also known as phagoptosis, also undergo a similar vacuole maturation sequence involving LC3 lipidation and lysosome fusion, but only HoCC involves mTOR-dependent regulation of vacuole maturation and cell death, similar to entosis. We further find that the regulation of apoptosis by mTOR involves the 4E-BP1 protein that is a known regulator of mRNA translation. The knockout of 4E-BP1 in engulfed cells rescues these cells from undergoing apoptosis caused by mTOR inhibition. These data identify amino acid signaling and the mTOR-4EBP-1 pathway as a survival pathway for live engulfed cells formed by entosis and HoCC. Together, my studies have uncovered novel roles of amino acid signaling in controlling cell death, and have identified, for ferroptosis, a potential new therapeutic strategy. |
