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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

Authors :
Kazuyoshi Funato
Kazuhiko Koike
Motoyuki Otsuka
Takahiro Seimiya
Yu Miyakawa
Eri Tanaka
Kazuma Sekiba
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.

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