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J. Biol. Chem., Vol. 281, Issue 5, 2676-2682, February 3, 2006

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

Vijaykumar R. Holla, Jason R. Mann, Qiong Shi, and Raymond N. DuBois, B.F. Byrd Professor of Molecular Oncology and the recipient of National Institutes of Health MERIT award R37-DK47297^¶1

From the Departments of Medicine and Cancer Biology, Vanderbilt University Medical Center and the ^¶Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232-6838

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 , 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.

Received for publication, July 18, 2005 , and in revised form, October 24, 2005.

^* This work was supported in part by United States Public Health Service Grants RO-DK-62112 and P0-CA-77839 and grants from the T. J. Martell Foundation and the National Colorectal Cancer Research Alliance (NCCRA). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 691 Preston Bldg., 2300 Pierce Ave., Nashville, TN 37232-6838. Tel.: 615-343-0527; Fax: 615-936-2697; E-mail: raymond.dubois{at}vanderbilt.edu.

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