title: Neutrophil gelatinase-associated lipocalin (NGAL) expression is dependent on the tumor-associated sigma-2 receptor S2RPgrmc1.
abstract: Tumor invasion is a critical step in the spread of cancer. S2R (sigma-2 receptor)/Pgrmc1 (progesterone receptor membrane component 1) is a cytochrome b(5)-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. S2R(Pgrmc1) markedly 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-9 activity 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(Pgrmc1) knock-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.
authors.affiliation: Department of Molecular and Biomedical Pharmacology, Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Shakeel U R
authors.initials: SU
authors.lastname: Mir
authors.forename: Ling
authors.initials: L
authors.lastname: Jin
authors.forename: Rolf J
authors.initials: RJ
authors.lastname: Craven
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000209:Acute-Phase Proteins / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D000071068:Lipocalin-2; D054834:Lipocalins / Q000096:biosynthesis* / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014183:Transplantation, Heterologous; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000209:Acute-Phase Proteins; D056572:Histone Deacetylase Inhibitors; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C115296:PGRMC1 protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; C498143:RELA protein, human; D011980:Receptors, Progesterone; D051996:Transcription Factor RelA; D020032:Tyrphostins; C101044:RTKI cpd; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1