title: Metabolic effect of TAp63α: enhanced glycolysis and pentose phosphate pathway, resulting in increased antioxidant defense.
abstract: TAp63α is a member of the p53 family, which plays a central role in epithelial cancers. Recently, a role has emerged for p53 family members in cancer metabolic modulation. In order to assess whether TAp63α plays a role in cancer metabolism, we exploited p53-null osteosarcoma Tet-On Saos-2 cells, in which the expression of TAp63α was dependent on doxycycline supplementation to the medium. Metabolomics labeling experiments were performed by incubating the cells in 13C-glucose or 13C15N-glutamine-labeled culture media, as to monitor metabolic fluxes upon induced expression of TAp63α. Induced expression of TAp63α resulted in cell cycle arrest at the G1 phase. From a metabolic standpoint, expression of Tap63α promoted glycolysis and the pentose phosphate pathway, which was uncoupled from nucleotide biosynthesis, albeit prevented oxidative stress in the form of oxidized glutathione. Double 13C-glucose and 13C15N-glutamine metabolic labeling confirmed that induced expression of TAp63α corresponded to a decreased flux of pyruvate to the Krebs cycle and decreased utilization of glutamine for catabolic purposes in the TCA cycle. Results were not conclusive in relation to anabolic utilization of labeled glutamine, since it is unclear to what extent the observed minor TAp63α-dependent increases of glutamine-derived labeling in palmitate could be tied to increased rates of reductive carboxylation and de novo synthesis of fatty acids. Finally, bioinformatics elaborations highlighted a link between patient survival rates and the co-expression of p63 and rate limiting enzymes of the pentose phosphate pathway, G6PD and PGD.
authors.affiliation: Department of Ecological and Biological Sciences, University of Tuscia, Largo dell'Università, snc, Viterbo, Italy. Department of Biochemistry and Molecular Genetics, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Angelo
authors.initials: A
authors.lastname: D'Alessandro
authors.affiliation: Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester University, Lancaster Road, Leicester, UK.
authors.forename: Ivano
authors.initials: I
authors.lastname: Amelio
authors.affiliation: CR-UK Beatson Institute, Switchback Road, Glasgow, UK. Current address: Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, Utrecht, The Netherlands.
authors.forename: Celia R
authors.initials: CR
authors.lastname: Berkers
authors.affiliation: Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester University, Lancaster Road, Leicester, UK.
authors.forename: Alexey
authors.initials: A
authors.lastname: Antonov
authors.affiliation: CR-UK Beatson Institute, Switchback Road, Glasgow, UK.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Vousden
authors.affiliation: Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester University, Lancaster Road, Leicester, UK. Biochemistry Laboratory IDI-IRCCS, c/o Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata", Via Montpellier 1, Rome, Italy. Institute of Cellular Biology and Neurobiology, CNR, Rome, Italy.
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.affiliation: Department of Ecological and Biological Sciences, University of Tuscia, Largo dell'Università, snc, Viterbo, Italy.
authors.forename: Lello
authors.initials: L
authors.lastname: Zolla
mesh_terms: D045744:Cell Line, Tumor; D019295:Computational Biology; D005434:Flow Cytometry; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D055432:Metabolomics; D009369:Neoplasms / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010427:Pentose Phosphate Pathway / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins