(505b) Multi-Omics Reveals That AKT but Not MYC Promotes Reactive Oxygen Species-Mediated Cell Death in Oxidative Culture
AIChE Annual Meeting
2020
2020 Virtual AIChE Annual Meeting
Food, Pharmaceutical & Bioengineering Division
Systems Biology of Cell Behavior: Experimental
Wednesday, November 18, 2020 - 8:15am to 8:30am
Results and Discussion: We tested how AKT and MYC affect the ability of cells to shift between respiration and glycolysis. Using immortalized mammary epithelial cells, we discovered that constitutively active AKT but not MYC induced cell death in galactose culture, where cells rely on oxidative phosphorylation for energy generation. However, the negative effects of AKT were temporary, and AKT-expressing cells recommenced growth after ~15 days in galactose. To identify the mechanisms regulating AKT-mediated cell death, we used metabolomics and found that AKT cells dying in galactose upregulated glutathione metabolism. Proteomic profiling revealed that AKT cells dying in galactose also upregulated nonsense-mediated mRNA decay, a marker of sensitivity to oxidative stress. We therefore measured levels of reactive oxygen species (ROS) and discovered that galactose induced ROS exclusively in cells expressing AKT. Furthermore, ROS were required for galactose-induced death of AKT-expressing cells.
Conclusions: Our findings highlight the importance of oncogene-dependent metabolic vulnerabilities in cancer cells and suggest that therapies targeting tumor metabolism will need to be appropriately paired with tumor genetic profiles.