The nerve growth factor I-B (NGFI-B) family of orphan receptors include NGFI-B? (Nur77, TR3), NGFI-B? (Nurr1), and NGFI-B? (Nor1), and ligands for NGFI-B proteins have not been reported. Apoptosis/differentiation inducing agents activate Nur77-dependent apoptosis via nuclear (transactivation) pathways or by nuclear-mitochondrial or nuclear-cytosolic translocation of Nur77. We have now identified for the first time at least three compounds that activate wild-type Nur77 in transactivation assays, and this response requires the ligand binding domain (LBD) of Nur77. The Nur77-active 1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methanes contain CF3 (DIM-C-pPhCF3), H (DIM-C-Ph), and OCH3 (DIM-C-pPhOCH3) substituents. These C-substituted diindolylmethanes (DIMs) induce apoptosis in pancreatic cancer cells through a nuclear pathway, and we hypothesize that C-substituted DIMs represent a unique class of ligands that activate Nur77 and induce apoptosis in pancreatic cancer cells.
In Aim 1, the structure-dependent activation of Nur77 by a series of ring- and phenyl-substituted derivatives of C-substituted DIMs will be determined in six pancreatic cancer cell lines that express Nur77 protein. The most active compounds (at least 3) will be used as prototypical Nur77 agonists for investigating ligand-dependent Nur77-DNA binding in electrophoretic mobility shift assay and ligand-induced Nur77-coactivator interactions and enhanced transactivation.
Aim 2 will focus on induction of apoptotic pathways by Nur77 agonists and compare these responses to those observed for apoptotic inducing agents (TPA, butyrate and the retinoid CD437) in selected pancreatic cancer cell lines. This approach will resolve apparent differences in previous reports and distinguish between ligand-activated Nur77 (nuclear) vs. extranuclear pathways for induction of apoptosis. Moreover, the molecular mechanisms of Nur77 agonist-induced expression of pro-apoptotic genes will also be investigated.
In Aim 3, the in vivo antitumorigenic activity of Nur77 agonists will be determined. The proposed studies will define the mechanism of action of Nur77 activation by selected C-substituted DIMs that are the first known ligands for this orphan receptor. These studies will serve to highlight the potential role of selective Nur77 modulators as a new class of chemotherapeutic drugs for treatment of pancreatic cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA124998-01A1
Application #
7320362
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Arya, Suresh
Project Start
2007-09-24
Project End
2012-07-31
Budget Start
2007-09-24
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$203,700
Indirect Cost
Name
Texas A&M University
Department
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
Safe, Stephen; Jin, Un-Ho; Hedrick, Erik et al. (2014) Minireview: role of orphan nuclear receptors in cancer and potential as drug targets. Mol Endocrinol 28:157-72
Lee, Syng-Ook; Jin, Un-Ho; Kang, Jeong Han et al. (2014) The orphan nuclear receptor NR4A1 (Nur77) regulates oxidative and endoplasmic reticulum stress in pancreatic cancer cells. Mol Cancer Res 12:527-538
Lee, Syng-Ook; Li, Xi; Hedrick, Erik et al. (2014) Diindolylmethane analogs bind NR4A1 and are NR4A1 antagonists in colon cancer cells. Mol Endocrinol 28:1729-39
Li, Xi; Lee, Syng-Ook; Safe, Stephen (2012) Structure-dependent activation of NR4A2 (Nurr1) by 1,1-bis(3'-indolyl)-1-(aromatic)methane analogs in pancreatic cancer cells. Biochem Pharmacol 83:1445-55
Lee, S-O; Andey, T; Jin, U-H et al. (2012) The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53. Oncogene 31:3265-76
Yoon, Kyungsil; Lee, Syng-Ook; Cho, Sung-Dae et al. (2011) Activation of nuclear TR3 (NR4A1) by a diindolylmethane analog induces apoptosis and proapoptotic genes in pancreatic cancer cells and tumors. Carcinogenesis 32:836-42
Lee, Syng-Ook; Li, Xi; Khan, Shaheen et al. (2011) Targeting NR4A1 (TR3) in cancer cells and tumors. Expert Opin Ther Targets 15:195-206
Roberts, Ruth A; Smith, Robert A; Safe, Stephen et al. (2010) Toxicological and pathophysiological roles of reactive oxygen and nitrogen species. Toxicology 276:85-94
Cho, Sung Dae; Lee, Syng-Ook; Chintharlapalli, Sudhakar et al. (2010) Activation of nerve growth factor-induced B alpha by methylene-substituted diindolylmethanes in bladder cancer cells induces apoptosis and inhibits tumor growth. Mol Pharmacol 77:396-404
Lee, Syng-Ook; Abdelrahim, Maen; Yoon, Kyungsil et al. (2010) Inactivation of the orphan nuclear receptor TR3/Nur77 inhibits pancreatic cancer cell and tumor growth. Cancer Res 70:6824-36

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