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 S2RPgrmc1-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. S2RPgrmc1 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. S2RPgrmc1 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 S2RPgrmc1knock-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 S2RPgrmc1 increases NGAL/LCN2 levels by activating NFκB via EGFR.
|Number of pages||8|
|Journal||Journal of Biological Chemistry|
|State||Published - Apr 27 2012|
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology