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Carcinogenesis Advance Access originally published online on July 1, 2009
Carcinogenesis 2009 30(9):1606-1613; 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, USA

* To whom correspondence should be addressed. Tel: +1 859 257 1837; Fax: +1 859 257 7585; Email: 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, [1S-[1{alpha}, 2{alpha} (Z), 3β (1E, 3S*), 4{alpha}]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo [2.2.1] hept-2-yl]-5-heptenoic acid (I-BOP), induced Nurr1 expression and stimulated proliferation of human lung cancer cells. Nurr1, an orphan nuclear receptor in the nuclear receptor subfamily 4A subfamily, has been implicated in cell proliferation, differentiation and apoptosis. I-BOP markedly induced Nurr1 messenger RNA and protein levels as compared with 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 protein kinase A (PKA)/cAMP response element binding (CREB), protein kinase C and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways and not related to epidermal growth factor receptor and prostaglandin E2 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 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.

Abbreviations: COX-2, cyclooxygenase; CRE, cAMP response element; CREB, cAMP response element binding; EP, prostaglandin E2 receptor; ERK, extracellular signal-regulated kinase; FBS, fetal bovine serum; FSK, forskolin; I-BOP, [1S-[1{alpha}, 2{alpha} (Z), 3β (1E, 3S*), 4{alpha}]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo [2.2.1] hept-2-yl]-5-heptenoic acid; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MEK1, mitogen activated protein kinase kinase 1; NF-{kappa}B, nuclear factor-kappa B; NR4A, nuclear receptor subfamily 4A; PCR, polymerase chain reaction; PGE2, prostaglandin E2; PKA, protein kinase A; PKC, protein kinase C; PI-3K, phosphatidylinositol 3-kinase; siRNA, small interfering RNA; TP, thromboxane A2 receptor; TXA2, thromboxane A2

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


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