European Cytokine Network

, Volume 27, Issue 4, pp 108–113 | Cite as

The co-regulators SRC-1 and SMRT are involved in interleukin-6-induced androgen receptor activation

  • Qi Wang
  • Hui Wang
  • Qiang Ju
  • Zhen Ding
  • Xing Ge
  • Qiao-Mei Shi
  • Ji-Long Zhou
  • Xiao-Long Zhou
  • Jin-Peng Zhang
  • Mei-Rong Zhang
  • Hong-Min Yu
  • Li-Chun Xu
Research Article



The androgen receptor (AR) can be stimulated by interleukin-6 (IL-6) in the absence of androgens to induce prostate cancer progression. The purpose of this study was to investigate whether the co-activator steroid receptor coactivator-1 (SRC-1) and co-repressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) are involved in IL-6-induced AR activation.


The effects of IL-6 on LNCaP cell proliferation were monitored using real-time cell analysis (RTCA) iCELLigence system. The impacts of IL-6 on the association of the AR with SRC-1 and SMRT were investigated using the mammalian two-hybrid assay.


IL-6 increased the proliferation of LNCaP cells with maximal induction at 50 ng/mL. The AR-SRC-1interaction was enhanced by IL-6, with maximal induction at the concentration of 50 ng/mL (P<0.05). IL-6 decreased theAR-SMRT interaction and a marked reduction was detected at 50 ng/mL (P<0.05).


IL-6 enhances LNCaP cells proliferation, which suggests that IL-6 might cause AR-positive prostate cancer growth through activation of the AR. The mechanism of IL-6-inducedARactivation is mediated through enhancing AR-SRC-1 interaction and inhibiting AR-SMRT interaction. We have shown a significant role for SRC-1 and SMRT in modulating IL-6-induced AR transactivation.

Key words

steroid receptor coactivator-1 silencing mediator for retinoid and thyroid hormone receptors androgen receptor interleukin-6 


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  1. 1.
    Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev 2004; 25: 276–308.CrossRefPubMedGoogle Scholar
  2. 2.
    Heinlein CA, Chang C. The roles of androgen receptors and androgen-binding proteins in non-genomic androgen actions. Mol Endocrinol 2002; 16: 2181–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Song LN, Herrell R, Byers S, Shah S, Wilson EM, Gelmann EP. Beta-catenin binds to the activation function 2 region of the androgen receptor and modulates the effects of the N-terminal domain and TIF2 on ligand-dependent transcription. Mol Cell Biol 2003; 23: 1674–87.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bolton EC, So AY, Chaivorapol C, Haqq CM, Li H, Yamamoto KR. Cell-and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev 2007; 21: 2005–17.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Suzuki H, Ueda T, Ichikawa T, Ito H. Androgen receptor involvement in the progression of prostate cancer. Endocr Relat Cancer 2003; 10: 209–16.CrossRefPubMedGoogle Scholar
  6. 6.
    Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to anti-androgen therapy. Nat Med 2004; 10: 33–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Lin DL, Whitney MC, Yao Z, Keller ET. Interleukin-6 induces androgen responsiveness in prostate cancer cells through upregulation of androgen receptor expression. Clin Cancer Res 2001; 7: 1773–81.PubMedGoogle Scholar
  8. 8.
    Sadar MD, Gleave ME. Ligand-independent activation of the androgen receptor by the differentiation agent butyrate in human prostate cancer cells. Cancer Res 2000; 60: 5825–31.PubMedGoogle Scholar
  9. 9.
    Kim HJ, Lee WJ. Ligand-independent activation of the androgen receptor by insulin-like growth factor-I and the role of the MAPK pathway in skeletal muscle cells. Mol Cells 2009; 28: 589–93.CrossRefPubMedGoogle Scholar
  10. 10.
    Hobisch A, Eder IE, Putz T, et al. Interleukin-6 regulates prostatespecific protein expression in prostate carcinoma cells by activation of the androgen receptor. Cancer Res 1998; 58: 4640–5.PubMedGoogle Scholar
  11. 11.
    Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol 1993; 54: 1–78.CrossRefPubMedGoogle Scholar
  12. 12.
    Lee SO, Lou W, Hou M, de Miguel F, Gerber L, Gao AC. Interleukin-6 promotes androgen-independent growth in LNCaP human prostate cancer cells. Clin Cancer Res 2003; 9: 370–6.PubMedGoogle Scholar
  13. 13.
    Adler HL, McCurdy MA, Kattan MW, Timme TL, Scardino PT, Thompson TC. Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. J Urol 1999; 161: 182–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Drachenberg DE, Elgamal AA, Rowbotham R, Peterson M, Murphy GP. Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate 1999; 41: 127–33.CrossRefPubMedGoogle Scholar
  15. 15.
    Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003; 374: 1–20.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Malinowska K, Neuwirt H, Cavarretta IT, et al. Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor. Endocr Relat Cancer 2009; 16: 155–69.CrossRefPubMedGoogle Scholar
  17. 17.
    Chen T, Wang LH, Farrar WL. Interleukin-6 activates androgen receptor-mediated gene expression through a signal transducer and activator of transcription 3-dependent pathway in LNCaP prostate cancer cells. Cancer Res 2000; 60: 2132–5.PubMedGoogle Scholar
  18. 18.
    Terakawa T, Miyake H, Furukawa J, Ettinger SL, Gleave ME, Fujisawa M. Enhanced sensitivity to androgen withdrawal due to overexpression of interleukin-6 in androgen-dependent human prostate cancer LNCaP cells. Br J Cancer 2009; 101: 1731–9.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Heinlein CA, Chang C. Androgen receptor (AR) coregulators: an overview. Endocr Rev 2002; 23: 175–200.CrossRefPubMedGoogle Scholar
  20. 20.
    McKenna NJ, Lanz RB, O’Malley BW. Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 1999; 20: 321–44.PubMedGoogle Scholar
  21. 21.
    Chmelar R, Buchanan G, Need EF, Tilley W, Greenberg NM. Androgen receptor coregulators and their involvement in the development and progression of prostate cancer. Int J Cancer 2007; 120: 719–33.CrossRefPubMedGoogle Scholar
  22. 22.
    Onate SA, Tsai SY, Tsai MJ, O’Malley BW. Sequence and characterization of a co-activator for the steroid hormone receptor superfamily. Science 1995; 270: 1354–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Fujimoto N, Mizokami A, Harada S, Matsumoto T. Different expression of androgen receptor co-activators in human prostate. Urology 2001; 58: 289–94.CrossRefPubMedGoogle Scholar
  24. 24.
    Gregory CW, He B, Johnson RT, et al. A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res 2001; 61: 4315–9.PubMedGoogle Scholar
  25. 25.
    Ueda T, Mawji NR, Bruchovsky N, Sadar MD. Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells. J Biol Chem 2002; 277: 38087–94.CrossRefPubMedGoogle Scholar
  26. 26.
    Jia L, Choong CS, Ricciardelli C, Kim J, Tilley WD, Coetzee GA. Androgen receptor signaling: mechanism of interleukin-6 inhibition. Cancer Res 2004; 64: 2619–26.CrossRefPubMedGoogle Scholar
  27. 27.
    Pan C, Liu YP, Li YF, et al. Effects of cypermethrin on the ligandindependent interaction between androgen receptor and steroid receptor coactivator-1. Toxicology 2012; 299: 160–4.CrossRefPubMedGoogle Scholar
  28. 28.
    Lin HK, Altuwaijri S, Lin WJ, Kan PY, Collins LL, Chang C. Proteasome activity is required for androgen receptor transcriptional activity via regulation of androgen receptor nuclear translocation and interaction with coregulators in prostate cancer cells. J Biol Chem 2002; 277: 36570–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Liao G, Chen LY, Zhang A, et al. Regulation of androgen receptor activity by the nuclear receptor co-repressor SMRT. J Biol Chem 2003; 278: 5052–61.CrossRefPubMedGoogle Scholar
  30. 30.
    Pan C, Wang Q, Liu YP, et al. Anti-androgen effects of the pyrethroid pesticide cypermethrin on interactions of androgen receptor with corepressors. Toxicology 2013; 311: 178–83.CrossRefPubMedGoogle Scholar
  31. 31.
    Solly K, Wang X, Xu X, Strulovici B, Zheng W. Application of real-time cell electronic sensing (RT-CES) technology to cell-based assays. Assay Drug Dev Technol 2004; 2: 363–72.CrossRefPubMedGoogle Scholar
  32. 32.
    Abassi YA, Xi B, Zhang W, et al. Kinetic cell-based morphological screening: prediction of mechanism of compound action and offtarget effects. Chem Biol 2009; 16: 712–23.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Giri D, Ozen M, Ittmann M. Interleukin-6 is an autocrine growth factor in human prostate cancer. Am J Pathol 2001; 159: 2159–65.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Debes JD, Schmidt LJ, Huang H, Tindall DJ. p300 mediates androgen-independent transactivation of the androgen receptor by interleukin-6. Cancer Res 2002; 62: 5632–6.PubMedGoogle Scholar
  35. 35.
    Dotzlaw H, Moehren U, Mink S, Cato AC, Iniguez Lluhi JA, Baniahmad A. The amino terminus of the human AR is target for co-repressor action and anti-hormone agonism. Mol Endocrinol 2002; 16: 661–73.CrossRefPubMedGoogle Scholar
  36. 36.
    Yoon HG, Wong J. The co-repressors silencing mediator of retinoid and thyroid hormone receptor and nuclear receptor co-repressor are involved in agonist-and antagonist-regulated transcription by androgen receptor. Mol Endocrinol 2006; 20: 1048–60.CrossRefPubMedGoogle Scholar
  37. 37.
    Janne OA, Moilanen AM, Poukka H, et al. Androgen-receptorinteracting nuclear proteins. Biochem Soc Trans 2000; 28: 401–5.CrossRefPubMedGoogle Scholar
  38. 38.
    Denmeade SR, Isaacs JT. A history of prostate cancer treatment. Nat Rev Cancer 2002; 2: 389–96.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Dotzlaw H, Papaioannou M, Moehren U, Claessens F, Baniahmad A. Agonist-antagonist induced co-activator and co-repressor interplay on the human androgen receptor. Mol Cell Endocrinol 2003; 213: 79–85.CrossRefPubMedGoogle Scholar
  40. 40.
    Edwards DP. The role of co-activators and co-repressors in the biology and mechanism of action of steroid hormone receptors. J Mammary Gland Biol Neoplasia 2000; 5: 307–24.CrossRefPubMedGoogle Scholar

Copyright information

© John Libbey Eurotext 2016

Authors and Affiliations

  • Qi Wang
    • 1
  • Hui Wang
    • 1
  • Qiang Ju
    • 1
  • Zhen Ding
    • 1
  • Xing Ge
    • 1
  • Qiao-Mei Shi
    • 1
  • Ji-Long Zhou
    • 1
  • Xiao-Long Zhou
    • 1
  • Jin-Peng Zhang
    • 1
  • Mei-Rong Zhang
    • 1
  • Hong-Min Yu
    • 1
  • Li-Chun Xu
    • 1
  1. 1.School of Public HealthXuzhou Medical College, XuzhouXuzhou, JiangsuChina

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