Prostaglandin E2 regulates the nuclear receptor NR4A2 in colorectal cancer

Vijaykumar R. Holla, Jason R. Mann, Qiong Shi, Raymond N. DuBois

    Research output: Contribution to journalArticlepeer-review

    85 Scopus citations

    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 PGE 2 target genes in colorectal carcinoma cells and report here that an immediate early gene, nuclear factor NR4A2 (Nurr1), is induced by PGE 2 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.Humancolorectal 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, amember of another family of nuclear receptors can stimulate progression of colorectal cancer downstream from cyclooxygenase 2-derived PGE2.

    Original languageEnglish (US)
    Pages (from-to)2676-2682
    Number of pages7
    JournalJournal of Biological Chemistry
    Volume281
    Issue number5
    DOIs
    StatePublished - Feb 3 2006

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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