title: A cell-surface β-hydroxylase is a biomarker and therapeutic target for hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) has a poor prognosis as a result of widespread intra- and extrahepatic metastases. There is an urgent need to understand signaling cascades that promote disease progression. Aspartyl-(asparaginyl)-β-hydroxylase (ASPH) is a cell-surface enzyme that generates enhanced cell motility, migration, invasion, and metastatic spread in HCC. We hypothesize that inhibition of its enzymatic activity could have antitumor effects. Small molecule inhibitors (SMIs) were developed based on the crystal structure of the ASPH catalytic site followed by computer-assisted drug design. Candidate compounds were tested for inhibition of β-hydroxylase activity and selected for their capability to modulate cell proliferation, migration, invasion, and colony formation in vitro and to inhibit HCC tumor growth in vivo using orthotopic and subcutaneous murine models. The biological effects of SMIs on the Notch signaling cascade were evaluated. The SMI inhibitor, MO-I-1100, was selected because it reduced ASPH enzymatic activity by 80% and suppressed HCC cell migration, invasion, and anchorage-independent growth. Furthermore, substantial inhibition of HCC tumor growth and progression was observed in both animal models. The mechanism(s) for this antitumor effect was associated with reduced activation of Notch signaling both in vitro and in vivo.
  
  
  CONCLUSIONS
  These studies suggest that the enzymatic activity of ASPH is important for hepatic oncogenesis. Reduced β-hydroxylase activity generated by the SMI MO-I-1100 leads to antitumor effects through inhibiting Notch signaling cascade in HCC. ASPH promotes the generation of an HCC malignant phenotype and represents an attractive molecular target for therapy of this fatal disease.
authors: Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI.
authors: Arihiro
authors: A
authors: Aihara
authors: Chiung-Kuei
authors: CK
authors: Huang
authors: Mark J
authors: MJ
authors: Olsen
authors: Qiushi
authors: Q
authors: Lin
authors: Waihong
authors: W
authors: Chung
authors: Qi
authors: Q
authors: Tang
authors: Xiaoqun
authors: X
authors: Dong
authors: Jack R
authors: JR
authors: Wands
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005663:Furans / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000503:physiopathology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013451:Sulfonic Acids / Q000494:pharmacology
chemical_list: D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D005663:Furans; C000594609:MO-I-1100; D008565:Membrane Proteins; D051880:Receptors, Notch; D013451:Sulfonic Acids; D006899:Mixed Function Oxygenases; C058291:aspartic acid 2-oxoglutarate-dependent dioxygenase