Targeting Aspartate Beta-Hydroxylase with the Small Molecule Inhibitor MO-I-1182 Suppresses Cholangiocarcinoma Metastasis

Dig Dis Sci. 2021 Apr;66(4):1080-1089. doi: 10.1007/s10620-020-06330-2. Epub 2020 May 22.

Abstract

Background: Cholangiocarcinoma is a devastating disease with a 2% 5-year survival if the disease has spread outside the liver. The enzyme aspartate beta-hydroxylase (ASPH) has been demonstrated to be highly expressed in cholangiocarcinoma but not in normal bile ducts and found to stimulate tumor cell migration. In addition, it was found that targeting ASPH inhibits cholangiocarcinoma malignant progression. However, it is not clear whether targeting ASPH with the small molecule inhibitor MO-I-1182 suppresses cholangiocarcinoma metastasis. The current study aims to study the efficacy of MO-I-1182 in suppressing cholangiocarcinoma metastasis.

Methods: The analysis was performed in vitro and in vivo with a preclinical animal model by using molecular and biochemical strategies to regulate ASPH expression and function.

Results: Knockdown of ASPH substantially inhibited cell migration and invasion in two human cholangiocarcinoma cell lines. Targeting ASPH with a small molecule inhibitor suppressed cholangiocarcinoma progression. Molecular mechanism studies demonstrated that knockdown of ASPH subsequently suppressed protein levels of the matrix metalloproteinases. The ASPH knockdown experiments suggest that this enzyme may modulate cholangiocarcinoma metastasis by regulating matrix metalloproteinases expression. Furthermore, using an ASPH inhibitor in a rat cholangiocarcinoma intrahepatic model established with BED-Neu-CL#24 cholangiocarcinoma cells, it was found that targeting ASPH inhibited intrahepatic cholangiocarcinoma metastasis and downstream expression of the matrix metalloproteinases.

Conclusion: ASPH may modulate cholangiocarcinoma metastasis via matrix metalloproteinases expression. Taken together, targeting ASPH function may inhibit intrahepatic cholangiocarcinoma metastasis and improve survival.

Keywords: Bile duct cancer; Cancer metastasis; Matrix metalloproteinase; Rat cholangiocarcinoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Ducts, Intrahepatic / metabolism
  • Bile Ducts, Intrahepatic / pathology
  • Calcium-Binding Proteins* / antagonists & inhibitors
  • Calcium-Binding Proteins* / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cholangiocarcinoma* / drug therapy
  • Cholangiocarcinoma* / metabolism
  • Cholangiocarcinoma* / pathology
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression
  • Gene Knockdown Techniques
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Matrix Metalloproteinases / metabolism
  • Membrane Proteins* / antagonists & inhibitors
  • Membrane Proteins* / metabolism
  • Mixed Function Oxygenases* / antagonists & inhibitors
  • Mixed Function Oxygenases* / metabolism
  • Muscle Proteins* / antagonists & inhibitors
  • Muscle Proteins* / metabolism
  • Neoplasm Metastasis / prevention & control*
  • Rats

Substances

  • Calcium-Binding Proteins
  • Enzyme Inhibitors
  • Membrane Proteins
  • Muscle Proteins
  • Mixed Function Oxygenases
  • ASPH protein, human
  • Matrix Metalloproteinases