title: TAp73 promotes anabolism.
abstract: Metabolic adaptation has emerged as a hallmark of cancer and a promising therapeutic target, as rapidly proliferating cancer cells adapt their metabolism increasing nutrient uptake and reorganizing metabolic fluxes to support biosynthesis. The transcription factor p73 belongs to the p53-family and regulates tumorigenesis via its two N-terminal isoforms, with (TAp73) or without (ΔNp73) a transactivation domain. TAp73 acts as tumor suppressor, at least partially through induction of cell cycle arrest and apoptosis and through regulation of genomic stability. Here, we sought to investigate whether TAp73 also affects metabolic profiling of cancer cells. Using high throughput metabolomics, we unveil a thorough and unexpected role for TAp73 in promoting Warburg effect and cellular metabolism. TAp73-expressing cells show increased rate of glycolysis, higher amino acid uptake and increased levels and biosynthesis of acetyl-CoA. Moreover, we report an extensive TAp73-mediated upregulation of several anabolic pathways including polyamine and synthesis of membrane phospholipids. TAp73 expression also increases cellular methyl-donor S-adenosylmethionine (SAM), possibly influencing methylation and epigenetics, and promotes arginine metabolism, suggestive of a role in extracellular matrix (ECM) modeling. In summary, our data indicate that TAp73 regulates multiple metabolic pathways that impinge on numerous cellular functions, but that, overall, converge to sustain cell growth and proliferation.
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK.
authors.forename: Ivano
authors.initials: I
authors.lastname: Amelio
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Antonov
authors.affiliation: Biochemistry Laboratory, IDI-IRCCS, University of Rome Tor Vergata, Rome 00133, Italy.
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: Catani
authors.affiliation: Biochemistry Laboratory, IDI-IRCCS, University of Rome Tor Vergata, Rome 00133, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Massoud
authors.affiliation: Biochemistry Laboratory, IDI-IRCCS, University of Rome Tor Vergata, Rome 00133, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bernassola
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Knight
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK. Biochemistry Laboratory, IDI-IRCCS, University of Rome Tor Vergata, Rome 00133, Italy. Molecular Pharmacology Laboratory, Technological University, St-Petersburg, Russia.
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK. Department of Cancer Studies, Cancer Research UK, Leicester Centre, University of Leicester, Leicester, LE1 7RH, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rufini
mesh_terms: D017209:Apoptosis / Q000502:physiology; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D008660:Metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human