Prostaglandin E2 Regulates the Nuclear Receptor NR4A2 in Colorectal Cancer

Vijaykumar R Holla,Jason R Mann,Qiong Shi,Raymond N Dubois

doi:10.1074/jbc.m507752200

Vijaykumar R Holla, Jason R Mann + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m507752200

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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 delta, 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.

Highlights

prostaglandin E2 (PGE2), the most abundant prostaglandin in colorectal cancer [19], can be generated from arachidonic acid by either COX-1 or COX-2
PGE2 Induces NR4A2 mRNA and Protein Expression in Colorectal Carcinoma Cells—To identify potential target genes for PGE2 in colorectal cancer, we performed microarray analysis on LS-174T cells treated with PGE2 (1 ␮M) at different time points
In confirmation of the microarray results, Northern blot analysis revealed that PGE2 rapidly induces NR4A2 expression (Fig. 1A)

Summary

Introduction

PGE2, the most abundant prostaglandin in colorectal cancer [19], can be generated from arachidonic acid by either COX-1 or COX-2. Our laboratory is actively investigating precisely which genes are regulated by PGE2 in colorectal cancer and during embryogenesis [21]. We show that expression and activity of NR4A2, a nuclear receptor superfamily member, are induced in colorectal carcinoma cells by PGE2. Transcription factors in the nuclear receptor superfamily regulate gene expression upon ligand binding [22, 23]. The type III group includes, among others, peroxisome proliferator-activated receptors and the NR4A family of receptors. We have identified key genes that are regulated by PGE2 in colorectal carcinoma cells. We present data suggesting that the nuclear receptor NR4A2 is regulated by PGE2 in colorectal cancer. This is the first demonstration that prostaglandins

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