DDRE-16. CYSTEINE IS AN ESSENTIAL AMINO ACID IN GLIOMAS

BACKGROUND: Cysteine is a non-essential amino acid, since it can be synthetized from methionine through the transsulfuration pathway; moreover, cysteine is also uptake from the diet as cystine. We have investigated the metabolism of cysteine in glioma cell lines, and how cysteine/cystine-deprivation alters their antioxidant response in addition to the effect of this nutrient restriction to viability and proliferation in vitro and in vivo. METHODS: Cysteine metabolism was investigated through LCMS-based (13)C-tracing experiments involving different probes such as (13)C-methyl-Methionine, (13)C-C3-Cysteine, (13)C-C3,3’-Cystine, (13)C-C3-Serine and (13)C-U-Glutamine and the expression levels of key enzymes in the transsulfuration pathway were also explored. Finally, a mouse model of IDH1 mutant glioma was subjected to a cysteine/cystine-free diet and tumor metabolism was analyzed by LCMS. RESULTS: We demonstrated that exogenous cysteine/cystine are crucial for glutathione synthesis, and impact growth and viability. We also found that methionine cycle is disconnected from the transsulfuration pathway based on (13)C-tracing data and protein expression levels of cystathionine synthase and cystathioninase. Accordingly, cysteine-related metabolites such as GSH, involved in REDOX hemostasis, are downregulated, revealing a hypersensitive phenotype to ROS. Animal models upon a cysteine/cystine-free diet experienced an increase in survival and elevated levels of oxidative stress in tumor tissue. CONCLUSION: This results presented herein reveal an alternative therapeutic approach combining cysteine/cysteine-deprivation diets and treatments involving ROS production by limiting the ability of glioma cells to quench oxidative stress through dietary interventions.