Prostaglandin E₂ Regulates the Nuclear Receptor NR4A2 in Colorectal Cancer^*

Abstract

Many lines of research implicate cyclooxygenase 2-derived prostaglandins in tumor growth and metastasis. More specifically, we have shown that prostaglandin E₂ (PGE₂) promotes cell proliferation and invasion through transactivation of the epidermal growth factor receptor, initiates immune evasion through induction of decay accelerating factor, and transactivates peroxisome proliferator-activated receptor δ, leading to increased polyp size and multiplicity. We continue to identify novel PGE₂ target genes in colorectal carcinoma cells and report here that an immediate early gene, nuclear factor NR4A2 (Nurr1), is induced by PGE₂ that in turn regulates cell death. Originally described as a critical dopaminergic neuron growth factor receptor, NR4A2 expression is rapidly but transiently induced by PGE₂ in a cAMP/protein kinase A-dependent manner. NR4A2 binds to the cognate NBRE response element and enhances transcription of a reporter construct in colorectal carcinoma cells. Furthermore, NR4A2 expression is elevated in Apc^-/+ mouse adenomas and its levels were further increased following PGE₂ treatment. Human colorectal cancers relative to matched normal mucosa showed increased NR4A2 expression. Although not previously described in epithelial tissues, NR4A2 protein localizes to proliferating crypts of Apc^-/+ mouse intestine. Finally, functional studies reveal that PGE₂-mediated protection from apoptosis is completely inhibited by a dominant-negative NR4A2 construct. Building on previous reports from our group on the peroxisome proliferator-activated receptor family of nuclear receptors, these most recent data suggest that NR4A2, a member of another family of nuclear receptors can stimulate progression of colorectal cancer downstream from cyclooxygenase 2-derived PGE₂.