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The fatty-acid amide hydrolase inhibitor URB597 inhibits MICA/B shedding
The fatty-acid amide hydrolase inhibitor URB597 inhibits MICA/B shedding
- Source :
- Scientific Reports, Vol 10, Iss 1, Pp 1-13 (2020), Scientific Reports
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group, 2020.
-
Abstract
- MICA/B proteins are expressed on the surface of various types of stressed cells, including cancer cells. Cytotoxic lymphocytes expressing natural killer group 2D (NKG2D) receptor recognize MICA/B and eliminate the cells. However, cancer cells evade such immune recognition by inducing proteolytic shedding of MICA/B proteins. Therefore, preventing the shedding of MICA/B proteins could enhance antitumor immunity. Here, by screening a protease inhibitor library, we found that the fatty-acid amide hydrolase (FAAH) inhibitor, URB597, suppresses the shedding of MICA/B. URB597 significantly reduced the soluble MICA level in culture medium and increased the MICA level on the surface of cancer cells. The effect was indirect, being mediated by increased expression of tissue inhibitor of metalloproteinases 3 (TIMP3). Knockdown of TIMP3 expression reversed the effect of URB597, confirming that TIMP3 is required for the MICA shedding inhibition by URB597. In contrast, FAAH overexpression reduced TIMP3 expression and the cell-surface MICA level and increased the soluble MICA level. These results suggest that inhibition of FAAH could prevent human cancer cell evasion of immune-mediated clearance.
- Subjects :
- Hepatitis B virus
Cell
lcsh:Medicine
Article
Amidohydrolases
Gastrointestinal cancer
chemistry.chemical_compound
Fatty acid amide hydrolase
Cell Line, Tumor
Neoplasms
medicine
Humans
Cytotoxic T cell
Tumour virus infections
Receptor
lcsh:Science
Tissue Inhibitor of Metalloproteinase-3
Multidisciplinary
Hepatitis C virus
Chemistry
Histocompatibility Antigens Class I
lcsh:R
Proteases
URB597
NKG2D
Molecular biology
Protease inhibitor (biology)
Culture Media
Gene Expression Regulation, Neoplastic
stomatognathic diseases
medicine.anatomical_structure
NK Cell Lectin-Like Receptor Subfamily K
Benzamides
Cancer cell
Tumour immunology
lcsh:Q
Carbamates
Post-translational modifications
T-Lymphocytes, Cytotoxic
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 10
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....0cce0f4e272c540f5d5543a9bf5c5798
- Full Text :
- https://doi.org/10.1038/s41598-020-72688-y