Targeting Aspartate Beta-Hydroxylase with the Small Molecule Inhibitor MO-I-1182 Suppresses Cholangiocarcinoma Metastasis
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Published on: July 21, 2018
Katsuya Nagaoka1, Kousuke Ogawa1, Chengcheng Ji1
1Liver Research Center, Division of Gastroenterology and Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, 55 Claverick St, Providence, RI, 02903, USA.
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.
Insights
Targeting aspartate beta-hydroxylase (ASPH) with MO-I-1182 inhibits cholangiocarcinoma metastasis by reducing matrix metalloproteinases. This approach may improve survival for cholangiocarcinoma patients.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Cholangiocarcinoma (CCA) has a poor prognosis, especially when metastatic.
- Aspartate beta-hydroxylase (ASPH) is overexpressed in CCA and promotes tumor cell migration.
- The role of ASPH in CCA metastasis requires further investigation.
Purpose of the Study:
- To evaluate the efficacy of the small molecule inhibitor MO-I-1182 in suppressing cholangiocarcinoma metastasis.
- To elucidate the molecular mechanisms by which ASPH influences CCA progression.
Main Methods:
- In vitro studies using human CCA cell lines.
- In vivo experiments utilizing a preclinical rat model of intrahepatic CCA.
- Molecular and biochemical analyses to assess ASPH expression and function.
Main Results:
- ASPH knockdown significantly inhibited migration and invasion of CCA cells.
- MO-I-1182 treatment suppressed CCA progression and intrahepatic metastasis in vivo.
- ASPH inhibition led to decreased matrix metalloproteinase (MMP) expression.
Conclusions:
- ASPH plays a critical role in modulating cholangiocarcinoma metastasis, potentially through regulating MMPs.
- Targeting ASPH with inhibitors like MO-I-1182 shows promise for inhibiting CCA metastasis.
- Inhibition of ASPH may represent a novel therapeutic strategy to improve survival in cholangiocarcinoma.
