Inhibition of triple negative breast cancer-associated inflammation and progression by N- acylethanolamine acid amide hydrolase (NAAA)

Abstract

Triple-negative breast cancer (TNBC) is associated with high mortality due to the high expression of pro-inflammatory cytokines and lack of targeted therapies. N-acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase that promotes inflammatory responses through the deactivation of Palmitoylethanolamide (PEA), an endogenous bioactive lipid mediator. Here, we examined NAAA expression in TNBC cells (MDA-MB-231 and MDA-MB-BrM2 cells) and the effects of NAAA inhibition on TNBC tumor growth, using a selective NAAA inhibitor AM11095 (IC₅₀ = 20 nM). TNBC cells expressed elevated levels of full-length and splice mRNAs naaa variants. TNBC cells also express the N-acyl ethanol amides and elevated levels of the two fatty acid cores arachidonic (AA) and docosahexaenoic (DHA). PEA or AM11095 inhibited the secretion of IL-6 and IL-8, reduced the activation of the NF-kB pathway, decreased the expression of VEGF and Placental growth factor (PLGF) in TNBCs, and inhibited tumor cell migration in vitro. Using cellular magnetic resonance imaging (MRI), body images of mice administered with human MDA-MB-BrM2 cells treated with AM11095 showed a significant decrease in tumor numbers with a lower volume of tumors and increased mice survival. Mice untreated or treated with vehicle control showed a high number of tumors with high volumes in multiple organs. Thus, NAAA inhibition may constitute a potential therapeutic approach in the management of TNBC-associated inflammation and tumor growth.