title: Aspartate β-Hydroxylase expression promotes a malignant pancreatic cellular phenotype.
abstract: Pancreatic cancer (PC) is one of the leading causes of cancer related deaths due to aggressive progression and metastatic spread. Aspartate β-hydroxylase (ASPH), a cell surface protein that catalyzes the hydroxylation of epidermal growth factor (EGF)-like repeats in Notch receptors and ligands, is highly overexpressed in PC. ASPH upregulation confers a malignant phenotype characterized by enhanced cell proliferation, migration, invasion and colony formation in vitro as well as PC tumor growth in vivo. The transforming properties of ASPH depend on enzymatic activity. ASPH links PC growth factor signaling cascades to Notch activation. A small molecule inhibitor of β-hydroxylase activity was developed and found to reduce PC growth by downregulating the Notch signaling pathway. These findings demonstrate the critical involvement of ASPH in PC growth and progression, provide new insight into the molecular mechanisms leading to tumor development and growth and have important therapeutic implications.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI, USA.|Current address: Department of Internal Medicine, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI, USA.|Current address: Department of Internal Medicine, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Qiushi
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Arihiro
authors.initials: A
authors.lastname: Aihara
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Chiung-Kuei
authors.initials: CK
authors.lastname: Huang
authors.affiliation: Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Waihong
authors.initials: W
authors.lastname: Chung
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI, USA.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Rolf
authors.initials: R
authors.lastname: Carlson
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Nadolny
authors.affiliation: Department of Chemistry and Biochemistry, Kennesaw State University, Kennesaw, GA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Gabriel
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy-Glendale, Midwestern University, Glendale, Arizona, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Olsen
authors.affiliation: Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Jack R
authors.initials: JR
authors.lastname: Wands
mesh_terms: D000818:Animals; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D010641:Phenotype; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D051881:Receptor, Notch1; D054852:Small Molecule Libraries; D006899:Mixed Function Oxygenases; C058291:aspartic acid 2-oxoglutarate-dependent dioxygenase