Abstract
The orphan nuclear receptor TR3 (NR41A and Nur77) is overexpressed in most lung cancer patients and is a negative prognostic factor for patient survival. The function of TR3 was investigated in non-small-cell lung cancer A549 and H460 cells, and knockdown of TR3 by RNA interference (siTR3) inhibited cancer cell growth and induced apoptosis. The prosurvival activity of TR3 was due, in part, to formation of a p300/TR3/ specificity protein 1 complex bound to GC-rich promoter regions of survivin and other Sp-regulated genes (mechanism 1). However, in p53 wild-type A549 and H460 cells, siTR3 inhibited the mTORC1 pathway, and this was due to activation of p53 and induction of the p53-responsive gene sestrin 2, which subsequently activated the mTORC1 inhibitor AMP-activated protein kinase α (AMPKα) (mechanism 2). This demonstrates that the pro-oncogenic activity of TR3 in lung cancer cells was due to inhibition of p53 and activation of mTORC1. 1,1-Bis(3’-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) is a recently discovered inhibitor of TR3, which mimics the effects of siTR3. DIM-C-pPhOH inhibited growth and induced apoptosis in lung cancer cells and lung tumors in murine orthotopic and metastatic models, and this was accompanied by decreased expression of survivin and inhibition of mTORC1 signaling, demonstrating that inactivators of TR3 represent a novel class of mTORC1 inhibitors.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Azoitei N, Pusapati GV, Kleger A, Moller P, Kufer R, Genze F et al. (2010). Protein kinase D2 is a crucial regulator of tumour cell-endothelial cell communication in gastrointestinal tumours. Gut 59: 1316–1330.
Bjornsti MA, Houghton PJ . (2004). The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4: 335–348.
Bras A, Albar JP, Leonardo E, de Buitrago GG, Martinez A . (2000). Ceramide-induced cell death is independent of the Fas/Fas ligand pathway and is prevented by Nur77 overexpression in A20 B cells. Cell Death Differ 7: 262–271.
Budanov AV, Karin M . (2008). p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTORC1 signaling. Cell 134: 451–460.
Chen L, Hu L, Chan TH, Tsao GS, Xie D, Huo KK et al. (2009). Chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1l) gene suppresses the nucleus-to-mitochondria translocation of nur77 to sustain hepatocellular carcinoma cell survival. Hepatology 50: 122–129.
Chen L, Yuan YF, Li Y, Chan TH, Zheng BJ, Huang J et al. (2010). Clinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion. Gut 60: 534–543.
Chintharlapalli S, Burghardt R, Papineni S, Ramaiah S, Yoon K, Safe S . (2005). Activation of Nur77 by selected 1,1-Bis(3’-indolyl)-1-(p-substituted phenyl)methanes induces apoptosis through nuclear pathways. J Biol Chem 280: 24903–24914.
Cho SD, Lee SO, Chintharlapalli S, Abdelrahim M, Khan S, Yoon K et al. (2010). Activation of nerve growth factor-induced Bα by methylene-substituted diindolylmethanes in bladder cancer cells induces apoptosis and inhibits tumor growth. Mol Pharmacol 77: 396–404.
Cho SD, Yoon K, Chintharlapalli S, Abdelrahim M, Pei P, Hamilton S et al. (2007). Nur77 agonists induce proapoptotic genes and responses in colon cancer cells through nuclear receptor-dependent and independent pathways. Cancer Res 67: 674–683.
Gronemeyer H, Gustafsson JA, Laudet V . (2004). Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3: 950–964.
Guertin DA, Sabatini DM . (2007). Defining the role of mTORC1 in cancer. Cancer Cell 12: 9–22.
Hay N, Sonenberg N . (2004). Upstream and downstream of mTORC1. Genes Dev 18: 1926–1945.
Ke N, Claassen G, Yu DH, Albers A, Fan W, Tan P et al. (2004). Nuclear hormone receptor NR4A2 is involved in cell transformation and apoptosis. Cancer Res 64: 8208–8212.
Kolluri SK, Bruey-Sedano N, Cao X, Lin B, Lin F, Han YH et al. (2003). Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells. Mol Cell Biol 23: 8651–8667.
Kolluri SK, Zhu X, Zhou X, Lin B, Chen Y, Sun K et al. (2008). A short Nur77-derived peptide converts Bcl-2 from a protector to a killer. Cancer Cell 14: 285–298.
Lee JH, Budanov AV, Park EJ, Birse R, Kim TE, Perkins GA et al. (2010a). Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 327: 1223–1228.
Lee SO, Abdelrahim M, Yoon K, Chintharlapalli S, Papineni S, Kim K et al. (2010b). Inactivation of the orphan nuclear receptor TR3/Nur77 inhibits pancreatic cancer cell and tumor growth. Cancer Res 70: 6824–6836.
Lee SO, Chintharlapalli S, Liu S, Papineni S, Cho SD, Yoon K et al. (2009). p21 Expression is induced by activation of nuclear nerve growth factor-induced Bα (NGFI-Bα, Nur77) in pancreatic cancer cells. Mol Cancer Res 7: 1169–1178.
Li H, Kolluri SK, Gu J, Dawson MI, Cao X, Hobbs PD et al. (2000). Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science 289: 1159–1164.
Li QX, Ke N, Sundaram R, Wong-Staal F . (2006). NR4A1, 2, 3--an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis. Histol Histopathol 21: 533–540.
Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X et al. (2004). Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 116: 527–540.
Liu JJ, Zeng HN, Zhang LR, Zhan YY, Chen Y, Wang Y et al. (2010). A unique pharmacophore for activation of the nuclear orphan receptor Nur77 in vivo and in vitro. Cancer Res 70: 3628–3637.
Maruyama K, Tsukada T, Bandoh S, Sasaki K, Ohkura N, Yamaguchi K . (1995). Expression of NOR-1 and its closely related members of the steroid/thyroid hormone receptor superfamily in human neuroblastoma cell lines. Cancer Lett 96: 117–122.
Maxwell MA, Muscat GE . (2006). The NR4A subgroup: immediate early response genes with pleiotropic physiological roles. Nucl Recept Signal 4: e002.
McKenna NJ, Cooney AJ, DeMayo FJ, Downes M, Glass CK, Lanz RB et al. (2009). Minireview: evolution of NURSA, the nuclear receptor signaling atlas. Mol Endocrinol 23: 740–746.
Milbrandt J . (1988). Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron 1: 183–188.
Pearen MA, Muscat GE . (2010). Minireview: nuclear hormone receptor 4A signaling: implications for metabolic disease. Mol Endocrinol 24: 1891–1903.
Shaw RJ, Cantley LC . (2006). Ras, PI(3)K and mTORC1 signalling controls tumour cell growth. Nature 441: 424–430.
She QB, Halilovic E, Ye Q, Zhen W, Shirasawa S, Sasazuki T et al. (2010). 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell 18: 39–51.
Wu H, Lin Y, Li W, Sun Z, Gao W, Zhang H et al. (2010). Regulation of Nur77 expression by {beta}-catenin and its mitogenic effect in colon cancer cells. FASEB J 25: 192–205.
Yang Q, Guan KL . (2007). Expanding mTORC1 signaling. Cell Res 17: 666–681.
Zeng H, Qin L, Zhao D, Tan X, Manseau EJ, Van HM et al. (2006). Orphan nuclear receptor TR3/Nur77 regulates VEGF-A-induced angiogenesis through its transcriptional activity. J Exp Med 203: 719–729.
Zhan Y, Du X, Chen H, Liu J, Zhao B, Huang D et al. (2008). Cytosporone B is an agonist for nuclear orphan receptor Nur77. Nat Chem Biol 4: 548–556.
Zhang XK . (2007). Targeting Nur77 translocation. Expert Opin Ther Targets 11: 69–79.
Zhao BX, Chen HZ, Lei NZ, Li GD, Zhao WX, Zhan YY et al. (2006). p53 mediates the negative regulation of MDM2 by orphan receptor TR3. EMBO J 25: 5703–5715.
Acknowledgements
This work was supported by National Institutes of Health (R01-CA124998) and the Texas A&M AgriLife.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Oncogene website
Supplementary information
Rights and permissions
About this article
Cite this article
Lee, SO., Andey, T., Jin, UH. et al. The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53. Oncogene 31, 3265–3276 (2012). https://doi.org/10.1038/onc.2011.504
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2011.504
Keywords
This article is cited by
-
Bis-indole-derived NR4A1 antagonists inhibit colon tumor and splenic growth and T-cell exhaustion
Cancer Immunology, Immunotherapy (2023)
-
The nuclear receptor 4A family members: mediators in human disease and autophagy
Cellular & Molecular Biology Letters (2020)
-
Nuclear receptor 4A2 (NR4A2) is a druggable target for glioblastomas
Journal of Neuro-Oncology (2020)
-
Dual targeting of Nur77 and AMPKα by isoalantolactone inhibits adipogenesis in vitro and decreases body fat mass in vivo
International Journal of Obesity (2019)
-
Potent inhibition of breast cancer by bis-indole-derived nuclear receptor 4A1 (NR4A1) antagonists
Breast Cancer Research and Treatment (2019)