Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 143, Issue 10, Pages 2575-2583Publisher
WILEY
DOI: 10.1002/ijc.31615
Keywords
a disintegrin and metalloprotease 17; hepatocellular carcinoma; MHC class I polypeptide-related sequence A; lomofungin
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology
- Gilead Sciences [24390184]
- Japan Agency for Medical Research and Development, Japan [15fk0310009h0004]
- GSK Japan Research Grant
- Gilead Sciences Research Grant
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In our previous study on hepatocellular carcinoma (HCC) susceptibility genes in chronic hepatitis patients, we identified the MHC class I polypeptide-related sequence A (MICA). Natural killer cells eliminate various cancer cells, including HCC, by suppressing MICA shedding. Therefore, we investigated MICA sheddases and inhibitors for HCC immunotherapy. In this study, HepG2, PLC/PRF/5, and Hep3B were treated with the siRNA of a disintegrin and metalloproteases (ADAMs) and matrix metalloproteases to measure the concentration of soluble MICA (sMICA) by ELISA to detect the therapeutic target. Furthermore, an FDA-approved drug library was tested for the enzymatic inhibition of the targeted enzyme in an in vitro drug screening assay system. ADAM17 knockdown reduced sMICA levels and increased membrane-bound MICA (mMICA) expression in HCC cells. In an in vitro drug screen using an FDA-approved drug library, lomofungin, an antifungal drug, was found to strongly decrease ADAM17 activity. In HCC cells, mMICA expression was induced and sMICA production was inhibited in a dose-dependent manner. These effects were cancelled upon ADAM17 knockdown, suggesting that lomofungin targeted ADAM17. Analysis of lomofungin analogs revealed the responsible functional groups. In summary, we suggest lomofungin to be an attractive agent for the immunological control of HCC, via the suppression of ADAM17.
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