1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol ameliorates EGF-induced MMP-9 expression by promoting receptor desensitization in MDA-MB-231 cells

Abstract

Activated epidermal growth factor receptors (EGFRs) are crucial for inducing metastasis in cancer cells by promoting matrix metalloproteinase (MMP) expression. The present study was designed to investigate the effects of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on MMP expression in epidermal growth factor (EGF)-stimulated breast cancer cells in vitro. EGF stimulation induced internalization of its cognate receptor, EGFR, for stimulus-desensitization. These internalized receptors, complexed with the ubiquitin ligase c-Cbl and EGFR pathway substrate 15 (EPS15) (for degradation), were evaluated by confocal microscopy at 5-90 min time intervals. During intracellular trafficking of EGFRs, EGF-induced signaling cascades were analyzed by examining EGFR and SHC phosphorylation. Modulation of MMP expression was assessed by evaluating the activity of transcription factor AP-1 using a luciferase assay. PLAG accelerated the assembly of EGFRs with c-Cbl and EPS15 and promoted receptor degradation. This faster intracellular EGFR degradation reduced AP-1-mediated MMP expression. PLAG stimulation upregulated thioredoxin-interacting protein (TXNIP) expression, and this mediated the accelerated receptor internalization. This PLAG-induced increase in EGFR trafficking was blocked in TXNIP-silenced cells. By downregulating MMP expression, PLAG effectively attenuated EGF-induced mobility and invasiveness in these cancer cells. These data suggest that PLAG may be a potential therapeutic agent for blocking metastasis.