title: Aspartate-β-hydroxylase (ASPH): A potential therapeutic target in human malignant gliomas.
abstract: BACKGROUND
  Despite therapeutic advances, survival with glioblastoma multiforme (GBM) remains below 15 months from diagnosis due to GBM's highly infiltrative nature which precludes complete surgical resection. Patient outcomes could potentially be improved by targeting genes and pathways that drive neoplastic cell motility and invasiveness, including hypoxia-inducible factor-1 (HIF-1α), NOTCH, and aspartate-β-hydroxylase (ASPH).
  
  
  METHODS
  Human astrocytoma biopsy specimens (n = 37), WHO Grades II-IV, were analyzed for levels and distributions of ASPH and HIF-1α immunoreactivity by immunohistochemical staining, and ASPH, Notch, JAG, HES1, HEY1 and HIF1α mRNA expression by quantigene multiplex analysis. The effects of small molecule inhibitors on ASPH's catalytic activity, cell viability and directional motility were examined in vitro in established GBM cell lines and primary tumor cells from an invasive mouse model of GBM.
  
  
  RESULTS
  The highest grade astrocytoma, i.e. GBM was associated with the highest levels of ASPH and HIF1α, and both proteins were more abundantly distributed in hypoxic compared with normoxic regions of tumor. Furthermore, mining of the TCGA database revealed higher levels of ASPH expression in the mesenchymal subtype of GBM, which is associated with more aggressive and invasive behavior. In contrast, lower grade astrocytomas had low expression levels of ASPH and HIF1α. In vitro experiments demonstrated that small molecule inhibitors targeting ASPH's catalytic activity significantly reduced GBM viability and directional motility. Similar effects occurred in GBM cells that were transduced with a lentiviral sh-ASPH construct.
  
  
  CONCLUSIONS
  This study demonstrates that increased ASPH expression could serve as a prognostic biomarker of gliomas and may assist in assigning tumor grade when biopsy specimens are scant. In addition, the findings suggest that GBM treatment strategies could be made more effective by including small molecule inhibitors of ASPH.
authors.affiliation: Liver Research Center, Providence, RI, United States; Department of Pathology, Providence, RI, United States; Department of Neurology, Providence, RI, United States; Department of Neurosurgery, Providence, RI, United States; Department of Medicine, Providence, RI, United States.
authors.forename: Lisa-Marie
authors.initials: LM
authors.lastname: Sturla
authors.affiliation: Liver Research Center, Providence, RI, United States; Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Tong
authors.affiliation: Department of Neurology, Providence, RI, United States.
authors.forename: Nick
authors.initials: N
authors.lastname: Hebda
authors.affiliation: Department of Medicine, Providence, RI, United States; Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, United States.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy-Glendale, Midwestern University, United States.
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Thomas
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy-Glendale, Midwestern University, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Olsen
authors.affiliation: Liver Research Center, Providence, RI, United States; Division of Gastroenterology, Providence, RI, United States; Division of Neuropathology, Providence, RI, United States; Department of Pathology, Providence, RI, United States; Department of Neurology, Providence, RI, United States; Department of Neurosurgery, Providence, RI, United States; Department of Medicine, Providence, RI, United States; Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, United States.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
keywords: Cancer Research; Cell biology; Genetics; Medicine; Neuroscience