LAUSR

Oncogenes can create metabolic vulnerabilities in cancer cells. 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. We then confirmed that galactose induced ROS-mediated cell death in breast cancer cells with upregulated AKT signaling. These results demonstrate that AKT but not MYC restricts the flexibility of cancer cells to use oxidative phosphorylation.