Fig. 3

SLC7A11 regulates nutrient dependency of cancer cells. This schematic represents cells with high expression of SLC7A11. a Under normal conditions, SLC7A11 exports large amounts of intracellular glutamate in exchange for extracellular cystine. Cystine imported by SLC7A11 is converted to cysteine that supports glutathione biosynthesis and ROS detoxification. However, SLC7A11-mediated glutamate export limits intracellular glutamate supply to the TCA cycle and mitochondrial respiration, rendering such cells more dependent on glucose and/or glutamine supply for survival and growth. Glutamine is the major precursor for glutamate. Glucose provides the major carbon source for the TCA cycle as well as NADPH for glutathione biosynthesis and ROS detoxification. b Under glucose-deprived conditions, cells with high expression of SLC7A11 lack adequate supplies to maintain the TCA cycle and mitochondrial respiration. In addition, cystine imported by SLC7A11 depletes NAPDH and induces ROS under glucose deprivation conditions, possibly because cystine conversion to cysteine consumes NADPH, which is largely provided by glucose. These events result in enhanced cell death of SLC7A11-high cancer cells under glucose starvation. OXPHOS oxidative phosphorylation, PPP pentose phosphate pathway, GLS glutaminase, αKG α-ketoglutarate, Cys cysteine