title: The metallophosphodiesterase Mpped2 impairs tumorigenesis in neuroblastoma.
abstract: Through microarray analyses, we identified the Mpped2 gene as differentially expressed in two neuroblastoma cell lines induced to differentiation with all-trans retinoic acid. Mpped2 codes for a new metallophosphodiesterase protein, the expression of which inhibits cell proliferation and soft agar colony formation in SH -SY5Y cells. This inhibition is concomitant to an increased proportion of the cells in G0/G1 phase and enhanced caspase 3 activation, effects not seen for the other phosphodiesterases. A Mpped2-null mutation (H67R) abrogates these functions, which indicates that the biochemical activity of Mpped2 is advantageous for cancer suppression. Expression analyses in the "Los Angeles" and "Essen" neuroblastoma gene-array data sets show that increased expression of Mpped2 is associated with good patient prognosis according to Kaplan-Meier analyses. Tumorigenic assays in mice show that overexpression of Mpped2 improves survival rate, substantially impairs tumor growth and induces neuronal differentiation. Altogether, these data show that Mpped2 expression impairs neuroblastoma tumorigenesis, and they establish a basis for future therapeutic applications.
authors.affiliation: CEINGE, Biotecnologie Avanzate; Naples, Italy and Department of Biochemistry and Medical Biotechnology; 'Federico II' University of Naples; Naples, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Liguori
authors.forename: Immacolata
authors.initials: I
authors.lastname: Andolfo
authors.forename: Paqualino
authors.initials: P
authors.lastname: de Antonellis
authors.forename: Veruska
authors.initials: V
authors.lastname: Aglio
authors.forename: Valeria
authors.initials: V
authors.lastname: di Dato
authors.forename: Natascia
authors.initials: N
authors.lastname: Marino
authors.forename: Nicola Ivan
authors.initials: NI
authors.lastname: Orlotti
authors.forename: Daniela
authors.initials: D
authors.lastname: De Martino
authors.forename: Mario
authors.initials: M
authors.lastname: Capasso
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Petrosino
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.forename: Luigi
authors.initials: L
authors.lastname: Navas
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.forename: Achille
authors.initials: A
authors.lastname: Iolascon
authors.forename: Massimo
authors.initials: M
authors.lastname: Zollo
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D016193:G1 Phase; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle; D014183:Transplantation, Heterologous; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D014212:Tretinoin; C561977:MPPED2 protein, human; D010727:Phosphoric Diester Hydrolases; D053148:Caspase 3