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Clinical and Translational Oncology

, Volume 20, Issue 10, pp 1302–1313 | Cite as

Nur77 suppression facilitates androgen deprivation-induced cell invasion of prostate cancer cells mediated by TGF-β signaling

  • J. Wu
  • H. Sun
  • X. Yang
  • X. Sun
Research Article
First Online:
Received:
Accepted:

Abstract

Background

Androgen deprivation therapy (ADT) remains a standard treatment for advanced prostate cancers. However, recent studies revealed that while inhibiting the growth of certain types of prostate cancer cells, ADT promotes invasion. In the current study, we explored the effects of Nur77, an orphan nuclear receptor, on prostate cancer cell invasion following ADT.

Methods

Androgen receptor (AR) and Nur77 protein expression in patient tissues and cell lines were quantified via ELISA and western blot. The effects of AR-signaling on Nur77 expression were examined. The effects of Nur77 over-expression and knockdown on ADT-induced prostate cancer cell invasion were characterized.

Results

The results showed that AR and Nur77 are both highly expressed in prostate cancers of patients. Nur77 is positively regulated by AR-signaling at transcriptional level in NCI-H660, a widely used prostate cancer cell line. AR antagonists, Casodex and MDV3100 treatment resulted in significant inhibition of prostate cancer cell growth but enhanced cancer cell invasion. Nur77 over-expression blocked invasion-promoting effect of ADT, which is consistent with the down-regulation of MMP9 and Snail protein expression. Further mechanistic investigations showed that Nur77 inhibited transcription of TGF-β target genes (Snail and MMP9), and thereby inhibits TGF-β-mediated prostate cancer cell invasion following androgen antagonism. In addition, our data suggested the nature of this inhibitory effect of Nur77 on TGF-β-signaling is selective, for Smad3-signaling, the classical effector of TGF-β-signaling, was not interrupted by Nur77 over-expression.

Conclusion

Considering the limited success of management of prostate cancer metastasis following ADT, our data strongly suggest that Nur77 regulation could be a promising direction for search of complementary therapeutic strategy on top of classic ADT therapy.

Keywords

Prostate cancer Androgen receptor Nur77 Androgen deprivation Cancer cell invasion 
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Notes

Acknowledgements

We thank the team of Urology Department of Nanjing First Hospital for the technical support in the whole research project.

Author contributions

WJ and SX designed the study, performed the experiments and drafted the manuscript. SX and SH revised the study protocol, supervised the whole project and revised the final draft. YX verified the analytical methods and made the revised draft.

Funding

This work was funded by Nanjing Medical Science and Technology Development Program (Serial No. ykk15904 to WJ).

Compliance with ethical standards

Conflict of interest

All authors agreed that there is nothing to disclose for the current study.

Ethical approval

The study protocol was approved by the Ethical Committee of Nanjing First Hospital in accordance with the Helsinki Declaration of 1975.

Informed consent

Patients were provided written informed consent prior to be enrolled into the study.

Supplementary material

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Supplementary material 4 (TIFF 2700 kb)

References

  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29.  https://doi.org/10.3322/caac.20138.CrossRefPubMedGoogle Scholar
  2. 2.
    Mohler JL, Kantoff PW, Armstrong AJ, Bahnson RR, Cohen M, D’Amico AV, et al. Prostate cancer, version 1.2014. J Natl Compr Cancer Netw : JNCCN. 2013;11(12):1471–9.CrossRefGoogle Scholar
  3. 3.
    Perlmutter MA, Lepor H. Androgen deprivation therapy in the treatment of advanced prostate cancer. Rev Urol. 2007;9(Suppl 1):S3–8.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Nouri M, Ratther E, Stylianou N, Nelson CC, Hollier BG, Williams ED. Androgen-targeted therapy-induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer: an opportunity for intervention. Front Oncol. 2014;4:370.  https://doi.org/10.3389/fonc.2014.00370.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Lin TH, Lee SO, Niu Y, Xu D, Liang L, Li L, et al. Differential androgen deprivation therapies with anti-androgens casodex/bicalutamide or MDV3100/Enzalutamide versus anti-androgen receptor ASC-J9(R) Lead to promotion versus suppression of prostate cancer metastasis. J Biol Chem. 2013;288(27):19359–69.  https://doi.org/10.1074/jbc.M113.477216.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Xie H, Li L, Zhu G, Dang Q, Ma Z, He D, et al. Infiltrated pre-adipocytes increase prostate cancer metastasis via modulation of the miR-301a/androgen receptor (AR)/TGF-beta1/Smad/MMP9 signals. Oncotarget. 2015;6(14):12326–39.  https://doi.org/10.18632/oncotarget.3619.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Wu J, Liu J, Jia R, Song H. Nur77 inhibits androgen-induced bladder cancer growth. Cancer Invest. 2013;31(10):654–60.  https://doi.org/10.3109/07357907.2013.853077.CrossRefPubMedGoogle Scholar
  8. 8.
    Maruyama K, Tsukada T, Ohkura N, Bandoh S, Hosono T, Yamaguchi K. The NGFI-B subfamily of the nuclear receptor superfamily (review). Int J Oncol. 1998;12(6):1237–43.PubMedGoogle Scholar
  9. 9.
    Mohan HM, Aherne CM, Rogers AC, Baird AW, Winter DC, Murphy EP. Molecular pathways: the role of NR4A orphan nuclear receptors in cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2012;18(12):3223–8.  https://doi.org/10.1158/1078-0432.CCR-11-2953.CrossRefGoogle Scholar
  10. 10.
    Ranhotra HS. The NR4A orphan nuclear receptors: mediators in metabolism and diseases. J Recept Signal Transduct Res. 2015;35(2):184–8.  https://doi.org/10.3109/10799893.2014.948555.CrossRefPubMedGoogle Scholar
  11. 11.
    Kolluri SK, Zhu X, Zhou X, Lin B, Chen Y, Sun K, et al. A short Nur77-derived peptide converts Bcl-2 from a protector to a killer. Cancer Cell. 2008;14(4):285–98.  https://doi.org/10.1016/j.ccr.2008.09.002.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Wilson AJ, Arango D, Mariadason JM, Heerdt BG, Augenlicht LH. TR3/Nur77 in colon cancer cell apoptosis. Can Res. 2003;63(17):5401–7.Google Scholar
  13. 13.
    Wu Q, Liu S, Ye XF, Huang ZW, Su WJ. Dual roles of Nur77 in selective regulation of apoptosis and cell cycle by TPA and ATRA in gastric cancer cells. Carcinogenesis. 2002;23(10):1583–92.CrossRefGoogle Scholar
  14. 14.
    Xie L, Jiang F, Zhang X, Alitongbieke G, Shi X, Meng M, et al. Honokiol sensitizes breast cancer cells to TNF-alpha induction of apoptosis by inhibiting Nur77 expression. Br J Pharmacol. 2016;173(2):344–56.  https://doi.org/10.1111/bph.13375.CrossRefPubMedGoogle Scholar
  15. 15.
    Lee KW, Cobb LJ, Paharkova-Vatchkova V, Liu B, Milbrandt J, Cohen P. Contribution of the orphan nuclear receptor Nur77 to the apoptotic action of IGFBP-3. Carcinogenesis. 2007;28(8):1653–8.  https://doi.org/10.1093/carcin/bgm088.CrossRefPubMedGoogle Scholar
  16. 16.
    Agostini-Dreyer A, Jetzt AE, Stires H, Cohick WS. Endogenous IGFBP-3 mediates intrinsic apoptosis through modulation of Nur77 phosphorylation and nuclear export. Endocrinology. 2015;156(11):4141–51.  https://doi.org/10.1210/en.2015-1215.CrossRefPubMedGoogle Scholar
  17. 17.
    Uemura H, Chang C. Antisense TR3 orphan receptor can increase prostate cancer cell viability with etoposide treatment. Endocrinology. 1998;139(5):2329–34.  https://doi.org/10.1210/endo.139.5.5969.CrossRefPubMedGoogle Scholar
  18. 18.
    Hu YL, Zhong D, Pang F, Ning QY, Zhang YY, Li G, et al. HNF1b is involved in prostate cancer risk via modulating androgenic hormone effects and coordination with other genes. Genet Mol Res GMR. 2013;12(2):1327–35.  https://doi.org/10.4238/2013.April.25.4.CrossRefPubMedGoogle Scholar
  19. 19.
    Feng X, Ma JW, Sun SQ, Guo HC, Yang YM, Jin Y, et al. Quantitative detection of the foot-and-mouth disease virus serotype O 146S antigen for vaccine production using a double-antibody sandwich ELISA and nonlinear standard curves. PLoS One. 2016;11(3):e0149569.  https://doi.org/10.1371/journal.pone.0149569.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Chen SL, Li YL, Tang Y, Chen ZC, Zhou J, Zhou J, et al. Development and evaluation of a double antibody sandwich ELISA for the detection of human sDC-SIGN. J Immunol Methods. 2016;436:16–21.  https://doi.org/10.1016/j.jim.2016.05.011.CrossRefPubMedGoogle Scholar
  21. 21.
    Wei CL, Lin YC, Chen TA, Lin RY, Liu TH. Respiration detection chip with integrated temperature-insensitive MEMS sensors and CMOS signal processing circuits. IEEE Trans Biomed Circuits Syst. 2015;9(1):105–12.  https://doi.org/10.1109/TBCAS.2014.2315532.CrossRefPubMedGoogle Scholar
  22. 22.
    Palumbo-Zerr K, Zerr P, Distler A, Fliehr J, Mancuso R, Huang J, et al. Orphan nuclear receptor NR4A1 regulates transforming growth factor-beta signaling and fibrosis. Nat Med. 2015;21(2):150–8.  https://doi.org/10.1038/nm.3777.CrossRefPubMedGoogle Scholar
  23. 23.
    Huggins C. Prostatic cancer treated by orchiectomy; the 5 year results. J Am Med Assoc. 1946;131:576–81.CrossRefGoogle Scholar
  24. 24.
    Harris WP, Mostaghel EA, Nelson PS, Montgomery B. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clin Pract Urol. 2009;6(2):76–85.  https://doi.org/10.1038/ncpuro1296.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Marques RB, Dits NF, Erkens-Schulze S, van Weerden WM, Jenster G. Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models. PLoS One. 2010;5(10):e13500.  https://doi.org/10.1371/journal.pone.0013500.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Niu Y, Chang TM, Yeh S, Ma WL, Wang YZ, Chang C. Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails. Oncogene. 2010;29(25):3593–604.  https://doi.org/10.1038/onc.2010.121.CrossRefPubMedGoogle Scholar
  27. 27.
    Niu Y, Altuwaijri S, Lai KP, Wu CT, Ricke WA, Messing EM, et al. Androgen receptor is a tumor suppressor and proliferator in prostate cancer. Proc Natl Acad Sci USA. 2008;105(34):12182–7.  https://doi.org/10.1073/pnas.0804700105.CrossRefPubMedGoogle Scholar
  28. 28.
    Son H, Moon A. Epithelial-mesenchymal transition and cell invasion. Toxicological Res. 2010;26(4):245–52.  https://doi.org/10.5487/TR.2010.26.4.245.CrossRefGoogle Scholar
  29. 29.
    Chou YT, Wang H, Chen Y, Danielpour D, Yang YC. Cited2 modulates TGF-beta-mediated upregulation of MMP9. Oncogene. 2006;25(40):5547–60.  https://doi.org/10.1038/sj.onc.1209552.CrossRefPubMedGoogle Scholar
  30. 30.
    Zhou F, Drabsch Y, Dekker TJ, de Vinuesa AG, Li Y, Hawinkels LJ, et al. Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-beta signalling. Nat Commun. 2014;5:3388.  https://doi.org/10.1038/ncomms4388.CrossRefPubMedGoogle Scholar
  31. 31.
    Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7(6):415–28.  https://doi.org/10.1038/nrc2131.CrossRefPubMedGoogle Scholar
  32. 32.
    Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 2002;3(3):155–66.  https://doi.org/10.1038/nrm757.CrossRefPubMedGoogle Scholar
  33. 33.
    Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2(2):84–9.  https://doi.org/10.1038/35000034.CrossRefPubMedGoogle Scholar
  34. 34.
    Qu SS, Huang Y, Zhang ZJ, Chen JQ, Lin RY, Wang CQ, et al. A 6 week randomized controlled trial with 4 week follow-up of acupuncture combined with paroxetine in patients with major depressive disorder. J Psychiatr Res. 2013;47(6):726–32.  https://doi.org/10.1016/j.jpsychires.2013.02.004.CrossRefPubMedGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2018

Authors and Affiliations

  1. 1.Department of Urology, Drum Tower HospitalMedical School of Nanjing UniversityNanjingChina
  2. 2.Department of Urology, Nanjing First HospitalNanjing Medical UniversityNanjingChina
  3. 3.Institute of Business AnalyticsUniversity of AlabamaTuscaloosaUSA

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