p73 regulates serine biosynthesis in cancer

Activation of serine biosynthesis supports growth and proliferation of cancer cells. Human cancers often exhibit overexpression ofphosphoglycerate dehydrogenase (PHGDH), the metabolic enzyme that catalyses the reaction that diverts serine biosynthesis fromthe glycolytic pathway. By refueling serine biosynthetic pathways, cancer cells sustain their metabolic requirements, promotingmacromolecule synthesis, anaplerotic flux and ATP. Serine biosynthesis intersects glutaminolysis and together with this pathwayprovides substrates for production of antioxidant GSH. In human lung adenocarcinomas we identified a correlation between serinebiosynthetic pathway and p73 expression. Metabolic profiling of human cancer cell line revealed that TAp73 activates serinebiosynthesis, resulting in increased intracellular levels of serine and glycine, associated to accumulation of glutamate, tricarboxylicacid (TCA) anaplerotic intermediates and GSH. However, at molecular level p73 does not directly regulate serine metabolicenzymes, but transcriptionally controls a key enzyme of glutaminolysis, glutaminase-2 (GLS-2). p73, through GLS-2, favorsconversion of glutamine in glutamate, which in turn drives the serine biosynthetic pathway. Serine and glutamate can be thenemployed for GSH synthesis, thus the p73-dependent metabolic switch enables potential response against oxidative stress. Inknockdown experiment, indeed, TAp73 depletion completely abrogates cancer cell proliferation capacity in serine/glycinedeprivation,supporting the role of p73 to help cancer cells under metabolic stress. These findings implicate p73 in regulation ofcancer metabolism and suggest that TAp73 influences glutamine and serine metabolism, affecting GSH synthesis and determiningcancer pathogenesis.