The fatty-acid amide hydrolase inhibitor URB597 inhibits MICA/B shedding
Kazuma Sekiba1,2, Motoyuki Otsuka3, Takahiro Seimiya1,2
1Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
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.
Insights
Fatty-acid amide hydrolase (FAAH) inhibition prevents cancer cells from shedding MICA/B proteins. This FAAH inhibitor increases MICA/B on cancer cells, enhancing immune recognition and potentially boosting antitumor immunity.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- MICA/B proteins on stressed cells, including cancer cells, are recognized by NKG2D receptors on cytotoxic lymphocytes.
- Cancer cells evade immune surveillance through proteolytic shedding of MICA/B proteins.
- Inhibiting MICA/B shedding could enhance antitumor immunity.
Purpose of the Study:
- To identify agents that prevent MICA/B shedding from cancer cells.
- To investigate the mechanism by which MICA/B shedding is inhibited.
Main Methods:
- Screening of a protease inhibitor library.
- Utilizing the fatty-acid amide hydrolase (FAAH) inhibitor URB597.
- Measuring soluble and cell-surface MICA levels.
- Investigating the role of tissue inhibitor of metalloproteinases 3 (TIMP3) via knockdown experiments.
- Examining the effects of FAAH overexpression.
Main Results:
- The FAAH inhibitor URB597 suppressed MICA/B shedding.
- URB597 reduced soluble MICA and increased cell-surface MICA levels.
- This effect was mediated by increased expression of TIMP3.
- TIMP3 knockdown reversed the URB597-mediated inhibition of MICA shedding.
- FAAH overexpression decreased TIMP3 and cell-surface MICA, increasing soluble MICA.
Conclusions:
- Inhibition of FAAH can prevent cancer cell immune evasion by suppressing MICA/B shedding.
- The mechanism involves upregulation of TIMP3, which is essential for MICA shedding inhibition.
- Targeting FAAH represents a potential strategy to enhance immune-mediated cancer clearance.
