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Carcinogenesis Advance Access published online on July 1, 2009
Carcinogenesis, doi:10.1093/carcin/bgp161
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Activation of Thromboxane A2 Receptors Induces Orphan Nuclear Receptor Nurr1 Expression and Stimulates Cell Proliferation in Human Lung Cancer Cells

Xiuling Li and Hsin-Hsiung Tai*

Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082

* To whom correspondence should be addressed: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082. Tel: 859-257-1837; Fax: 859-257-7585; E-mail: htai1{at}uky.edu

Previous studies implicate that activation of thromboxane A2 receptor (TP) induced cell proliferation and transformation in several cell lines. We report here that the activation of TP by its agonist, I-BOP, induced Nurr1 expression and stimulated proliferation of human lung cancer cells. Nurr1, an orphan nuclear receptor in the NR4A subfamily, has been implicated in cell proliferation, differentiation, and apoptosis. I-BOP markedly induced Nurr1 mRNA and protein levels as compared to other subfamily members, Nur77 and Nor-1. The signaling pathways of I-BOP-induced Nurr1 expression were examined by using various inhibitors of signaling molecules. The induction of Nurr1 expression by I-BOP appeared to be mediated through PKA/CREB, PKC and MAPK/ERK pathways and not related to EGFR and PGE2 pathways. Transcriptional activation of Nurr1 gene by I-BOP was further investigated at the promoter level in H157 cells. 5’-Deletion analysis, site-directed mutagenesis, and luciferase reporter assay demonstrated that Nurr1 expression was induced by I-BOP in a PKA/CREB-dependent manner. Further studies have revealed that Nurr1 may mediate cyclin D1 expression and I-BOP-induced cell proliferation in H157 cells since small interfering RNA (siRNA) of Nurr1 blocked I-BOP-induced cyclin D1 expression and cell proliferation and also decreased cell growth rate. These results provide strong evidence that Nurr1 plays a significant role in cell proliferation and may mediate TP agonist-induced proliferation in lung cancer cells.

Key Words: Thromboxane A2 Receptors • Prostaglandins • Nuclear Receptors • Nurr1 • Cell Proliferation • Lung Cancer

Received March 14, 2009; revised June 2, 2009; accepted June 20, 2009.


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