Neutrophil gelatinase-associated lipocalin (NGAL) expression is dependent on the tumor-associated sigma-2 receptor S2R^Pgrmc1

Tumor invasion is a critical step in the spread of cancer. S2R (sigma-2 receptor)/Pgrmc1 (progesterone receptor membrane component 1) is a cytochrome b₅-related drug-binding orphan receptor essential for tumor formation and invasion. Secretory proteins drive these processes, so we screened for S2R^Pgrmc1-dependent secreted proteins using antibody arrays. S2 ^RPgrmc1markedly regulated the expression of NGAL/LCN2 (neutrophil gelatinase-associated lipocalin/lipocalin 2), a secreted glycoprotein that binds to MMP-9 (matrix metalloproteinase 9) and protects it from degradation. S2R^Pgrmc1 knock-down blocked NGAL/LCN2 expression at the protein and RNA levels and decreased MMP9 activity. NGAL expression was required for MMP-9activity and tumor formation. S2R^Pgrmc1 associates with EGFR and increases EGFR levels at the plasma membrane, and the EGFR inhibitors erlotinib and AG1478, as well as Akt and ERK inhibitors, suppressed the NGAL/LCN2 RNA and protein levels. NGAL is transcriptionally regulated by NFκB, and S2R ^Pgrmc1 knock-down decreased the NFκB subunit p65/RelA acetylation, phosphorylation, and activation. In S2R^Pgrmc1knock-down cells, p65 acetylation was reversed by inhibitors of histone deacetylase 1, and the inhibitors partially restored NGAL levels. Our results are consistent with a model in which S2R^Pgrmc1 increases NGAL/LCN2 levels by activating NFκB via EGFR.