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Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77

Oncogene volume 31, pages 2653–2667 (2012)Cite this article

Abstract

Dysregulation of β-catenin turnover due to mutations of its regulatory proteins including adenomatous polyposis coli (APC) and p53 is implicated in the pathogenesis of cancer. Thus, intensive effort is being made to search for alternative approaches to reduce abnormally activated β-catenin in cancer cells. Nur77, an orphan member of the nuclear receptor superfamily, has a role in the growth and apoptosis of cancer cells. Here, we reported that Nur77 could inhibit transcriptional activity of β-catenin by inducing β-catenin degradation via proteasomal degradation pathway that is glycogen synthase kinase 3β and Siah-1 independent. Nur77 induction of β-catenin degradation required both the N-terminal region of Nur77, which was involved in Nur77 ubiquitination, and the C-terminal region, which was responsible for β-catenin binding. Nur77/ΔDBD, a Nur77 mutant lacking its DNA-binding domain, resided in the cytoplasm, interacted with β-catenin, and induced β-catenin degradation, demonstrating that Nur77-mediated β-catenin degradation was independent of its DNA binding and transactivation, and might occur in the cytoplasm. In addition, we reported our identification of two digitalis-like compounds (DLCs), H-9 and ATE-i2-b4, which potently induced Nur77 expression and β-catenin degradation in SW620 colon cancer cells expressing mutant APC protein in vitro and in animals. DLC-induced Nur77 protein was mainly found in the cytoplasm, and inhibition of Nur77 nuclear export by the CRM1-dependent nuclear export inhibitor leptomycin B or Jun N-terminal kinase inhibitor prevented the effect of DLC on inducing β-catenin degradation. Together, our results demonstrate that β-catenin can be degraded by cytoplasmic Nur77 through their interaction and identify H-9 and ATE-i2-b4 as potent activators of the Nur77-mediated pathway for β-catenin degradation.

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References

  • Camacho CP, Latini FR, Oler G, Hojaij FC, Maciel RM, Riggins GJ et al. (2009). Down-regulation of NR4A1 in follicular thyroid carcinomas is restored following lithium treatment. Clin Endocrinol (Oxf) 70: 475–483.

    Article  CAS  Google Scholar 

  • Cao X, Liu W, Lin F, Li H, Kolluri SK, Lin B et al. (2004). Retinoid X receptor regulates Nur77/TR3-dependent apoptosis by modulating its nuclear export and mitochondrial targeting. Mol Cell Biol 24: 9705–9725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chao LC, Bensinger SJ, Villanueva CJ, Wroblewski K, Tontonoz P . (2008). Inhibition of adipocyte differentiation by Nur77, Nurr1, and Nor1. Mol Endocrinol 22: 2596–2608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cho SD, Yoon K, Chintharlapalli S, Abdelrahim M, Lei P, Hamilton S et al. (2007). Nur77 agonists induce proapoptotic genes and responses in colon cancer cells through nuclear receptor-dependent and nuclear receptor-independent pathways. Cancer Res 67: 674–683.

    Article  CAS  PubMed  Google Scholar 

  • Chtarbova S, Nimmrich I, Erdmann S, Herter P, Renner M, Kitajewski J et al. (2002). Murine Nr4a1 and Herpud1 are up-regulated by Wnt-1, but the homologous human genes are independent from beta-catenin activation. Biochem J 367: 723–728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dawson MI, Hobbs PD, Peterson VJ, Leid M, Lange CW, Feng KC et al. (2001). Apoptosis induction in cancer cells by a novel analogue of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid lacking retinoid receptor transcriptional activation activity. Cancer Res 61: 4723–4730.

    CAS  PubMed  Google Scholar 

  • Dillard AC, Lane MA . (2007). Retinol decreases beta-catenin protein levels in retinoic acid-resistant colon cancer cell lines. Mol Carcinog 46: 315–329.

    Article  CAS  PubMed  Google Scholar 

  • Dillard AC, Lane MA . (2008). Retinol increases beta-catenin-RXRalpha binding leading to the increased proteasomal degradation of beta-catenin and RXRalpha. Nutr Cancer 60: 97–108.

    Article  CAS  PubMed  Google Scholar 

  • Forman BM, Umesono K, Chen J, Evans RM . (1995). Unique response pathways are established by allosteric interactions among nuclear hormone receptors. Cell 81: 541–550.

    Article  CAS  PubMed  Google Scholar 

  • Fu M, Wang C, Li Z, Sakamaki T, Pestell RG . (2004). Minireview: cyclin D1: normal and abnormal functions. Endocrinology 145: 5439–5447.

    Article  CAS  PubMed  Google Scholar 

  • Han YH, Cao X, Lin B, Lin F, Kolluri SK, Stebbins J et al. (2006). Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt. Oncogene 25: 2974–2986.

    Article  CAS  PubMed  Google Scholar 

  • Hart M, Concordet JP, Lassot I, Albert I, del los Santos R, Durand H et al. (1999). The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell. Curr Biol 9: 207–210.

    Article  CAS  PubMed  Google Scholar 

  • Hutchinson DA, Mori A, Savitzky AH, Burghardt GM, Wu X, Meinwald J et al. (2007). Dietary sequestration of defensive steroids in nuchal glands of the Asian snake Rhabdophis tigrinus. Proc Natl Acad Sci USA 104: 2265–2270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ilyas M, Tomlinson IP, Rowan A, Pignatelli M, Bodmer WF . (1997). Beta-catenin mutations in cell lines established from human colorectal cancers. Proc Natl Acad Sci USA 94: 10330–10334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang MM, Dai Y, Gao H, Zhang X, Wang GH, He JY et al. (2008). Cardenolides from Antiaris toxicaria as potent selective Nur77 modulators. Chem Pharm Bull (Tokyo) 56: 1005–1008.

    Article  CAS  Google Scholar 

  • Katagiri Y, Takeda K, Yu ZX, Ferrans VJ, Ozato K, Guroff G . (2000). Modulation of retinoid signalling through NGF-induced nuclear export of NGFI-B. Nat Cell Biol 2: 435–440.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Kitagawa H, Ray WJ, Glantschnig H, Nantermet PV, Yu Y, Leu CT et al. (2007). A regulatory circuit mediating convergence between Nurr1 transcriptional regulation and Wnt signaling. Mol Cell Biol 27: 7486–7496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klein PS, Melton DA . (1996). A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 93: 8455–8459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kolluri SK, Cao X, Bruey-Sedano N, Lin B, Lin F, Han Y et al. (2003). Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells. Mol Cell Biol 23: 8651–8667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kudo N, Matsumori N, Taoka H, Fujiwara D, Schreiner EP, Wolff B et al. (1999). Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region. Proc Natl Acad Sci USA 96: 9112–9117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee SO, Abdelrahim M, Yoon K, Chintharlapalli S, Papineni S, Kim K et al. (2010). Inactivation of the orphan nuclear receptor TR3/Nur77 inhibits pancreatic cancer cell and tumor growth. Cancer Res 70: 6824–6836.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Liang B, Song X, Liu G, Li R, Xie J, Xiao L et al. (2007). Involvement of TR3/Nur77 translocation to the endoplasmic reticulum in ER stress-induced apoptosis. Exp Cell Res 313: 2833–2844.

    Article  CAS  PubMed  Google Scholar 

  • Lin B, Kolluri S, 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.

    Article  CAS  PubMed  Google Scholar 

  • Liu C, Kato Y, Zhang Z, Do VM, Yankner BA, He X . (1999). beta-Trcp couples beta-catenin phosphorylation-degradation and regulates Xenopus axis formation. Proc Natl Acad Sci USA 96: 6273–6278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Stevens J, Rote CA, Yost HJ, Hu Y, Neufeld KL et al. (2001). Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. Mol Cell 7: 927–936.

    Article  CAS  PubMed  Google Scholar 

  • Liu ZG, Smith SW, McLaughlin KA, Schwartz LM, Osborne BA . (1994). Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate-early gene nur77. Nature 367: 281–284.

    Article  CAS  PubMed  Google Scholar 

  • Logan CY, Nusse R . (2004). The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20: 781–810.

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Lazaro M . (2007). Digitoxin as an anticancer agent with selectivity for cancer cells: possible mechanisms involved. Expert Opin Ther Targets 11: 1043–1053.

    Article  CAS  PubMed  Google Scholar 

  • Matsuzawa SI, Reed JC . (2001). Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. Mol Cell 7: 915–926.

    Article  CAS  PubMed  Google Scholar 

  • Maxwell MA, Muscat GE . (2006). The NR4A subgroup: immediate early response genes with pleiotropic physiological roles. Nucl Recept Signal 4: e002.

    Article  PubMed  PubMed Central  Google Scholar 

  • Moon RT, Bowerman B, Boutros M, Perrimon N . (2002). The promise and perils of Wnt signaling through beta-catenin. Science 296: 1644–1646.

    Article  CAS  PubMed  Google Scholar 

  • Mullican SE, Zhang S, Konopleva M, Ruvolo V, Andreeff M, Milbrandt J et al. (2007). Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nat Med 13: 730–735.

    Article  CAS  PubMed  Google Scholar 

  • Nesher M, Shpolansky U, Rosen H, Lichtstein D . (2007). The digitalis-like steroid hormones: new mechanisms of action and biological significance. Life Sci 80: 2093–2107.

    Article  CAS  PubMed  Google Scholar 

  • Peifer M . (1997). Beta-catenin as oncogene: the smoking gun. Science 275: 1752–1753.

    Article  CAS  PubMed  Google Scholar 

  • Peifer M, Polakis P . (2000). Wnt signaling in oncogenesis and embryogenesis–a look outside the nucleus. Science 287: 1606–1609.

    Article  CAS  PubMed  Google Scholar 

  • Philips A, Lesage S, Gingras R, Maira MH, Gauthier Y, Hugo P et al. (1997). Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol 17: 5946–5951.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Polakis P . (2000). Wnt signaling and cancer. Genes Dev 14: 1837–1851.

    CAS  PubMed  Google Scholar 

  • Polakis P . (2007). The many ways of Wnt in cancer. Curr Opin Genet Dev 17: 45–51.

    Article  CAS  PubMed  Google Scholar 

  • Ramaswamy S, Ross KN, Lander ES, Golub TR . (2003). A molecular signature of metastasis in primary solid tumors. Nat Genet 33: 49–54.

    Article  CAS  PubMed  Google Scholar 

  • Safe S, Papineni S, Chintharlapalli S . (2008). Cancer chemotherapy with indole-3-carbinol, bis(3′-indolyl)methane and synthetic analogs. Cancer Lett 269: 326–338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shipp MA, Ross KN, Tamayo P, Weng AP, Kutok JL, Aguiar RC et al. (2002). Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 8: 68–74.

    Article  CAS  PubMed  Google Scholar 

  • Steyn PS, van Heerden FR . (1998). Bufadienolides of plant and animal origin. Nat Prod Rep 15: 397–413.

    Article  CAS  PubMed  Google Scholar 

  • Uemura H, Chang C . (1998). Antisense TR3 orphan receptor can increase prostate cancer cell viability with etoposide treatment. Endocrinology 139: 2329–2334.

    Article  CAS  PubMed  Google Scholar 

  • Ward RD, Weigel NL . (2009). Steroid receptor phosphorylation: assigning function to site-specific phosphorylation. Biofactors 35: 528–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson AJ, Arango D, Mariadason JM, Heerdt BG, Augenlicht LH . (2003). TR3/Nur77 in colon cancer cell apoptosis. Cancer Res 63: 5401–5407.

    CAS  PubMed  Google Scholar 

  • Wilson TE, Fahrner TJ, Johnston M, Milbrandt J . (1991). Identification of the DNA binding site for NGFI-B by genetic selection in yeast. Science 252: 1296–1300.

    Article  CAS  PubMed  Google Scholar 

  • Woronicz JD, Calnan B, Ngo V, Winoto A . (1994). Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature 367: 277–281.

    Article  CAS  PubMed  Google Scholar 

  • Wu F, Mo YY . (2007). Ubiquitin-like protein modifications in prostate and breast cancer. Front Biosci 12: 700–711.

    Article  CAS  PubMed  Google Scholar 

  • Wu H, Lin Y, Li W, Sun Z, Gao W, Zhang H et al. (2011). Regulation of Nur77 expression by {beta}-catenin and its mitogenic effect in colon cancer cells. FASEB J 25: 192–205.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wu Q, Dawson MI, Zheng Y, Hobbs PD, Agadir A, Jong L et al. (1997a). Inhibition of trans-retinoic acid-resistant human breast cancer cell growth by retinoid X receptor-selective retinoids. Mol Cell Biol 17: 6598–6608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Q, Li Y, Liu R, Agadir A, Lee MO, Liu Y et al. (1997b). Modulation of retinoic acid sensitivity in lung cancer cells through dynamic balance of orphan receptors nur77 and COUP-TF and their heterodimerization. Embo J 16: 1656–1669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiao JH, Ghosn C, Hinchman C, Forbes C, Wang J, Snider N et al. (2003). Adenomatous polyposis coli (APC)-independent regulation of beta-catenin degradation via a retinoid X receptor-mediated pathway. J Biol Chem 278: 29954–29962.

    Article  CAS  PubMed  Google Scholar 

  • Yochum GS, Cleland R, McWeeney S, Goodman RH . (2007). An antisense transcript induced by Wnt/beta-catenin signaling decreases E2F4. J Biol Chem 282: 871–878.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Zhang XK . (2007). Targeting Nur77 translocation. Expert Opin Ther Targets 11: 69–79.

    Article  CAS  PubMed  Google Scholar 

  • Zhao HY, Wu FK, Qiu YK, Wu Z, Jiang YT, Chen JY . (2010). Studies on cytotoxic constituents from the skin of the toad Bufo bufo gargarizans. J Asian Nat Prod Res 12: 793–800.

    Article  CAS  PubMed  Google Scholar 

  • Zhao Y, Bruemmer D . (2010). NR4A orphan nuclear receptors: transcriptional regulators of gene expression in metabolism and vascular biology. Arterioscler Thromb Vasc Biol 30: 1535–1541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou H, Liu W, Su Y, Wei Z, Liu J, Kolluri SK et al. (2010). NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling. Cancer Cell 17: 560–573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr Zhuohua Zhang for providing β-catenin expression vectors and TOPFLASH reporter plasmid. This work is in part supported by grants from the National Institutes of Health (CA140980, GM089927), the US Army Medical Research and Material Command, the 985 Project from Xiamen University, the National Natural Science Foundation of China (NSFC; 30971445 and NSCF-81001373) and NSFC/Hong Kong Research Grants Council (RGC; 30931160431) and the Natural Science Foundation of Fujian Province (2009J01198).

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  1. School of Pharmaceutical Sciences, Xiamen University, Xiamen, China

    Z Sun, Y Qiu, H Zhou, L Chen, B Qin, H Wu, F Jiang, J Liu, H-F Chen, Z Wu & J-Z Zeng

  2. Sanford-Burnham Medical Research Institute, La Jolla, CA, USA

    X Cao, H Zhou, J Chen, J Liu, Q-Y Hu & X-K Zhang

  3. Guangdong Pharmaceutical University, Guangzhou, China

    M-M Jiang

  4. Institutes of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou, China

    Y Dai & X-S Yao

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Sun, Z., Cao, X., Jiang, MM. et al. Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77. Oncogene 31, 2653–2667 (2012). https://doi.org/10.1038/onc.2011.448

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