Cyclooxygenase-2-derived prostaglandin E2 stimulates Id-1 transcription.
Cyclooxygenase-2 (COX-2) and Id-1 are overexpressed in a variety of human malignancies. Recently, each of these genes was found to play a role in mediating breast cancer metastasis to the lungs, but their potential interdependence was not evaluated. Hence, the main objective of the current study was to determine whether COX-2-derived prostaglandin (PGE(2)) activated Id-1 transcription, leading in turn to increased invasiveness of mammary epithelial cells. In MDA-MB-231 cells, treatment with PGE(2) induced Id-1, an effect that was mimicked by an EP(4) agonist. PGE(2) via EP(4) activated the epidermal growth factor receptor (EGFR) --> ERK1/2 pathway, which led to increased expression of Egr-1. PGE(2) stimulated EGFR signaling by inducing the release of amphiregulin, an EGFR ligand. The ability of PGE(2) to activate Id-1 transcription was mediated by enhanced binding of Egr-1 to the Id-1 promoter. Silencing of COX-2 or pharmacological inhibition of COX-2 led to reduced PGE(2) production, decreased Id-1 expression, and reduced migration of cells through extracellular matrix. A similar decrease in cell migration was found when Id-1 was silenced. The interrelationship between COX-2, PGE(2), Id-1, and cell invasiveness was also compared in nontumorigenic SCp2 and tumorigenic SCg6 mammary epithelial cells. Consistent with the findings in MDA-MB-231 cells, COX-2-derived PGE(2) induced Id-1, leading in turn to increased cell invasiveness. Taken together, these results suggest that PGE(2) via EP(4) activated the EGFR --> ERK1/2 --> Egr-1 pathway, leading to increased Id-1 transcription and cell invasion. These findings provide new insights into the relationship between COX-2 and Id-1 and their potential role in metastasis.
Department of Medicine and the Weill Cornell Cancer Center, Weill Cornell Medical College, NY, NY 10065, USA. ksubba@med.cornell.edu
Kotha
K
Subbaramaiah
Robert
R
Benezra
Clifford
C
Hudis
Andrew J
AJ
Dannenberg
D001483:Base Sequence; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D012337:RNA, Ribosomal, 18S / Q000737:chemistry; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction; D014158:Transcription, Genetic
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; C545650:PTGER4 protein, human; D012337:RNA, Ribosomal, 18S; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D015232:Dinoprostone