title: p73 regulates serine biosynthesis in cancer.
abstract: Activation of serine biosynthesis supports growth and proliferation of cancer cells. Human cancers often exhibit overexpression of phosphoglycerate dehydrogenase (PHGDH), the metabolic enzyme that catalyses the reaction that diverts serine biosynthesis from the glycolytic pathway. By refueling serine biosynthetic pathways, cancer cells sustain their metabolic requirements, promoting macromolecule synthesis, anaplerotic flux and ATP. Serine biosynthesis intersects glutaminolysis and together with this pathway provides substrates for production of antioxidant GSH. In human lung adenocarcinomas we identified a correlation between serine biosynthetic pathway and p73 expression. Metabolic profiling of human cancer cell line revealed that TAp73 activates serine biosynthesis, resulting in increased intracellular levels of serine and glycine, associated to accumulation of glutamate, tricarboxylic acid (TCA) anaplerotic intermediates and GSH. However, at molecular level p73 does not directly regulate serine metabolic enzymes, but transcriptionally controls a key enzyme of glutaminolysis, glutaminase-2 (GLS-2). p73, through GLS-2, favors conversion of glutamine in glutamate, which in turn drives the serine biosynthetic pathway. Serine and glutamate can be then employed for GSH synthesis, thus the p73-dependent metabolic switch enables potential response against oxidative stress. In knockdown experiment, indeed, TAp73 depletion completely abrogates cancer cell proliferation capacity in serine/glycine-deprivation, supporting the role of p73 to help cancer cells under metabolic stress. These findings implicate p73 in regulation of cancer metabolism and suggest that TAp73 influences glutamine and serine metabolism, affecting GSH synthesis and determining cancer pathogenesis.
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK.
authors.forename: I
authors.initials: I
authors.lastname: Amelio
authors.affiliation: The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ, USA.
authors.forename: E K
authors.initials: EK
authors.lastname: Markert
authors.affiliation: 1] Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK [2] Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Rufini
authors.affiliation: 1] Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK [2] Molecular Pharmacology Laboratory, Technological University, St-Petersburg, Russia.
authors.forename: A V
authors.initials: AV
authors.lastname: Antonov
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK.
authors.forename: B S
authors.identifier: 0000000323051970
authors.initials: BS
authors.lastname: Sayan
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK.
authors.forename: P
authors.initials: P
authors.lastname: Tucci
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Agostini
authors.affiliation: Division of Thoracic Surgery, University of Tor Vergata, Rome, Italy.
authors.forename: T C
authors.initials: TC
authors.lastname: Mineo
authors.affiliation: The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Levine
authors.affiliation: 1] Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK [2] Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Melino
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005972:Glutaminase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D009687:Nuclear Proteins / Q000502:physiology*; D050543:Phosphoglycerate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D020033:Protein Isoforms / Q000502:physiology; D012694:Serine / Q000096:biosynthesis*; D000637:Transaminases / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D012694:Serine; D050543:Phosphoglycerate Dehydrogenase; D000637:Transaminases; C022393:phosphoserine aminotransferase; D010744:Phosphoric Monoester Hydrolases; C022394:phosphoserine phosphatase; C586504:GLS2 protein, human; D005972:Glutaminase