Role of IL-6 in Regulating the Androgen Receptor



Androgen receptor (AR) is expressed in human prostate cancer in which it could be activated by steroid hormones and nonsteroidal compounds. Interleukin-6 (IL-6) levels are increased in tissues and sera from patients with advanced prostate cancer. AR-negative prostate cancer cell lines express high levels of IL-6. This cytokine may activate signaling pathways of Janus kinase/signal transducers and activators of transcription factors or mitogen-activated protein kinase, thus contributing to tumor cell growth. IL-6 activation of the AR was described by several investigators in various cell lines. This regulation of AR activity is of importance for cellular differentiation, as evidenced by increase of prostate-specific antigen expression. It was shown that the N-terminal region of the AR is required for activation by IL-6. The effect of IL-6 also depends on functional coactivators SRC-1 and p300. Interestingly, cells exposed to a chronic treatment with IL-6 acquire a more malignant phenotype and downregulate AR expression. Further studies are necessary to evaluate whether IL-6/AR axis could be targeted by novel therapies in prostate cancer.


Prostate Cancer Androgen Receptor LNCaP Cell Prostate Cancer Cell Line Androgen Receptor Expression 
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  1. Agoulnik IU, Vaid A, Bingman WEr, Erdeme H, Frolov A, Smith CL, Ayala G, Ittmann M, Weigel NL(2005)Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression. Cancer Res65: 7959–7967PubMedGoogle Scholar
  2. Akakura K, Suzuki H, Ueda T, Komiya A, Ichikawa T, Igarashi T, Ito H(2003)Possible mechanism of dexamethasone therapy for prostate cancer: suppression of circulating level of interleukin-6. Prostate56: 106–109PubMedCrossRefGoogle Scholar
  3. Bellezza I, Neuwirt H, Nemes C, Cavarretta IT, Puhr M, Steiner H, Minelli A, Bartsch G, Offner F, Hobisch A, Doppler W, Culig Z(2006)Suppressor of cytokine signaling-3 antagonizes cAMP effects on proliferation and apoptosis and is expressed in human prostate cancer. Am J Pathol169: 2199–2208PubMedCrossRefGoogle Scholar
  4. Bellido T, Jilka RL, Boyce BF, Girasole G, Broxmeyer H, Dalrymple SA, Murray R, Manolagas SC(1995)Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. J Clin Invest95: 2886–2895PubMedCrossRefGoogle Scholar
  5. Blasczyk N, Masri BA, Mawji NR, Ueda T, McAlinden G, Duncan CP, Bruchovsky N, Schweikert HU, Schnabel D, Jones EC, Sadar MD(2004)Osteoblast-derived factors induce androgen-independent proliferation and expression of prostate-specific antigen in human prostate cancer cells. Clin Cancer Res10: 1860–1869CrossRefGoogle Scholar
  6. Campbell CL, Jiang Z, Savarese DM, Savarese TM(2001)Increased expression of the interleukin-11 receptor and evidence of STAT3 activation in prostate carcinoma. Am J Pathol158: 25–32PubMedCrossRefGoogle Scholar
  7. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vess R, Rosenfeld MG, Sawyers CL(2004)Molecular determinants of resistance to antiandrogen therapy. Nat Med10: 33–39PubMedCrossRefGoogle Scholar
  8. Comuzzi B, Nemes C, Schmidt S, Jasarevic Z, Lodde M, Pycha A, Bartsch G, Offner F, Culig Z, Hobisch A(2004)The androgen receptor co-activator CBP is up-regulated following androgen withdrawal and is highly expressed in advanced prostate cancer. J Pathol204: 159–166PubMedCrossRefGoogle Scholar
  9. Craft N, Shostak Y, Carey M, Sawyers CL(1999)A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med5: 280–285PubMedCrossRefGoogle Scholar
  10. Culig Z, Hobisch A, Cronauer MV, Radmayr C, Trapman J, Hittmair A, Bartsch G, Klocker H(1994)Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res54: 5474–5478PubMedGoogle Scholar
  11. Culig Z, Steiner H, Bartsch G, Hobisch A(2005)Interleukin-6 regulation of prostate cancer cell growth. J Cell Biochem95: 497–505PubMedCrossRefGoogle Scholar
  12. De Marzo AM, Platz EA, Sutcliffe S, Xu J, Grönberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG(2007)Inflammation in prostate carcinogenesis. Nat Rev Cancer7: 256–269PubMedCrossRefGoogle Scholar
  13. Debes JD, Schmidt LJ, Huang H, Tindall DJ(2002)p300 mediates interleukin-6-dependent transactivation of the androgen receptor. Cancer Res62: 5632–5636PubMedGoogle Scholar
  14. Debes JD, Sebo TJ, Lohse CM, Murphy LM, Haugen de AL, Tindall DJ(2003)p300 in prostate cancer proliferation and progression. Cancer Res63: 7638–7640PubMedGoogle Scholar
  15. Debes JD, Comuzzi B, Schmidt LJ, Dehm SM, Culig Z, Tindall DJ(2005)p300 regulates androgen receptor-independent expression of prostate-specific antigen in prostate cancer cells treated chronically with interleukin-6. Cancer Res65: 5965–5973PubMedCrossRefGoogle Scholar
  16. Degeorges A, Tatoud R, Fauvel Lafeve F, Podgorniak MP, Millot G, de Cremoux P, Calvo F(1996)Stromal cells from human benign prostate hyperplasia produce a growth-inhibitory factor for LNCaP prostate cancer cells, identified as interleukin-6. Int J Cancer68: 207–214PubMedCrossRefGoogle Scholar
  17. Desai SJ, Ma AH, Tepper CG, Chen HW, Kung HJ(2006)Inappropriate activation of the androgen receptor by nonsteroids: involvement of the Src kinase pathway and its therapeutic implications. Cancer Res66: 10449–10459PubMedCrossRefGoogle Scholar
  18. Eder IE, Culig Z, Ramoner R, Thurnher M, Putz T, Nessler-Menardi C, Tiefenthaler M, Bartsch G, Klocker H(2000)Inhibition of LNCaP prostate cancer cells by means of androgen receptor antisense oligonucleotides. Cancer Gene Therapy7: 997–1007PubMedCrossRefGoogle Scholar
  19. Fradet V, Lessard L, Begin L, Karakiewicz P, Masson AM, Saad F(2004)Nuclear factor-kappa B nuclear localization is predictive of biochemical recurrence in patients with positive margin prostate cancer. Clin Cancer Res10: 8460–8464PubMedCrossRefGoogle Scholar
  20. George DJ, Halabi S, Shepard TF, Sanford B, Vogelzang NJ, Small EJ, Kantoff PW(2005)The prognostic significance of plasma interleukin-6 levels in patients with metastatic hormone-refractory prostate cancer: results from cancer and leukemia group B 9480. Clin Cancer Res11: 1815–1820PubMedCrossRefGoogle Scholar
  21. Giri D, Ozen M, Ittmann M(2001)Interleukin-6 is an autocrine growth factor in human prostate cancer. Am J Pathol159: 2159–2165PubMedCrossRefGoogle Scholar
  22. Godoy-Tundidor S, Hobisch A, Pfeil K, Bartsch G, Culig Z(2002)Acquisition of agonistic properties of nonsteroidal antiandrogens after treatment with oncostatin M in prostate cancer cells. Clin Cancer Res8: 2356–2361PubMedGoogle Scholar
  23. Gupta S, Afaq F, Mukhtar H(2002)Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. Oncogene21: 3727–3738PubMedCrossRefGoogle Scholar
  24. He B, You L, Uematsu K, Zang K, Xu Z, Lee AY, Costello JF, McCormick F, Jablons DM(2003)SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci USA100: 14133–14138PubMedCrossRefGoogle Scholar
  25. Hobisch A, Eder IE, Putz T, Horninger W, Bartsch G, Klocker H, Culig Z(1998)Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. Cancer Res58: 4640–4645PubMedGoogle Scholar
  26. Hobisch A, Rogatsch H, Hittmair A, Fuchs D, Bartsch GJ, Klocker H, Bartsch G, Culig Z(2000)Immunohistochemical localization of interleukin-6 and its receptor in benign, premalignant and malignant prostate tissue. J Pathol191: 239–244PubMedCrossRefGoogle Scholar
  27. Hobisch A, Ramoner R, Fuchs D, Godoy-Tundidor S, Bartsch G, Klocker H, Culig Z(2001)Prostate cancer cells (LNCaP) generated after long-term interleukin-6 treatment express interleukin-6 and acquire an interleukin-6-partially resistant phenotype. Clin Cancer Res7: 2941–2948PubMedGoogle Scholar
  28. Jia L, Kim J, Shen H, Clark PE, Tilley WD, Coetzee GA(2003)Androgen receptor activity at the prostate specific antigen locus: steroidal and non-steroidal mechanisms. Mol Cancer Res1: 385–392PubMedGoogle Scholar
  29. Jia L, Choong CS, Ricciardelli C, Kim J, Tilley WD, Coetzee GA(2004)Androgen receptor signaling: mechanism of interleukin-6 inhibition. Cancer Res64: 2619–2626PubMedCrossRefGoogle Scholar
  30. Kim O, Jiang T, Xie Y, Guo Z, Chen H, Qiu Y(2004)Synergism of cytoplasmic kinases in IL6-induced ligand-independent activation of androgen receptor in prostate cancer cells. Oncogene23: 1838–1844PubMedCrossRefGoogle Scholar
  31. Lee SO, Lou W, Hou M, Onate SA, Gao AC(2003)Interleukin-4 enhances prostate-specific antigen expression by activation of the androgen receptor and Akt pathway. Oncogene22: 6037–6044Google Scholar
  32. Lee SQ, Chun JY, Nadiminty N, Lou W, Gao AC(2007)Interleukin-6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression. Prostate67: 764–773PubMedCrossRefGoogle Scholar
  33. Lin DL, Whitney MC, Yao Z, Keller ET(2001)Interleukin-6 induces androgen responsiveness in prostate cancer cells through up-regulation of androgen receptor expression. Clin Cancer Res7: 1773–1781PubMedGoogle Scholar
  34. Lin HK, Hu YC, Yang L, Altuwaijri S, Chen YT, Kang HY, Chang C(2004)Suppression vs induction of androgen receptor functions by the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer LNCaP cells with different passage numbers. J Biol Chem278: 50902–50907CrossRefGoogle Scholar
  35. Matsuda T, Junicho A, Yamamoto T, Kishi H, Korkmaz K, Saatcioglu F, Fuse H, Muraguchi A(2001)Cross-talk between signal transducer and activator of transcription 3 and androgen receptor signaling in prostate carcinoma cells. Biochem Biophys Res Commun283: 179–187PubMedCrossRefGoogle Scholar
  36. Mora LB, Buettner R, Seigne J, Diaz J, Ahmad N, Garcia R, Bowman T, Falcone R, Fairclough R, Cantor A, Muro-Cacho C, Livingston S, Karras J, Pow-Sang J, Jove R(2002)Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res62: 6659–6666PubMedGoogle Scholar
  37. Mori S, Murakami-Mori K, Bonavida B(1999)Oncostatin M (OM) promotes the growth of DU 145 human prostate cancer cells, but not PC-3 or LNCaP, through the signaling of the OM specific receptor. Anticancer Res19: 1011–1015PubMedGoogle Scholar
  38. Nakashima J, Tachibana M, Horiguchi Y, Oya M, Ohigashi T, Asakura H, Murai M(2000)Serum interleukin-6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res6: 2702–2706PubMedGoogle Scholar
  39. Nazareth LV, Weigel NL(1996)Activation of the human androgen receptor through a protein kinase A signaling pathway. J Biol Chem271: 19900–19907PubMedCrossRefGoogle Scholar
  40. Neuwirt H, Puhr M, Cavarretta IT, Mitterberger M, Hobisch A, Culig Z(2007)Suppressor of cytokine signalling-3 is up-regulated by androgen in prostate cancer cell lines and inhibits androgen-mediated proliferation and secretion. Endocr Relat Cancer14: 1007–1019PubMedCrossRefGoogle Scholar
  41. Niwa Y, Kanda H, Shikauchi Y, Saiura A, Matsubara K, Kitagawa T, Yamamoto J, Kubo T, Yoshikawa H(2005)Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene24: 6406–6417PubMedGoogle Scholar
  42. Okamoto M, Lee C, Oyasu R(1997)Interleukin-6 as a paracrine and autocrine growth factor in human prostatic carcinoma cells in vitro. Cancer Res57: 141–146PubMedGoogle Scholar
  43. Park JI, Lee MG, Cho K, Park BJ, Chae KS, Byun DS, Ryu BK, Park YK, Chi SG(2003)Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cell through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways. Oncogene22: 4314–4332PubMedCrossRefGoogle Scholar
  44. Royuela M, Ricote M, Parsons MS, Garcia-Tunon I, Paniagua R, de Miguel MP(2004)Immunohistochemical analysis of the IL-6 family of cytokines and their receptors in benign, hyperplastic, and malignant human prostate. J Pathol202: 41–49PubMedCrossRefGoogle Scholar
  45. Sadar MD, Gleave ME(2000)Ligand-independent activation of the androgen receptor by the differentiation agent butyrate in human prostate cancer cells. Cancer Res60: 5825–5831PubMedGoogle Scholar
  46. Santhanam U, Ray A, Sehgal PB(1991)Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product. Proc Natl Acad Sci USA88: 7605–7609PubMedCrossRefGoogle Scholar
  47. Sartorius CA, Tung T, Takimoto GS, Horwitz KB(1993)Antagonist-occupied human progesterone receptors bound to DNA are functionally switched to transcriptional agonists by cAMP. J Biol Chem268: 9262–9266PubMedGoogle Scholar
  48. Shariat SF, Andrews B, Kattan MW, Kim J, Wheeler T, Slawin KM(2001)Plasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasis. Urology58: 1008–1015PubMedCrossRefGoogle Scholar
  49. Smith PC, Keller ET(2001)Anti-interleukin-6 monoclonal antibody induces regression of human prostate cancer xenografts in nude mice. Prostate48: 47–53PubMedCrossRefGoogle Scholar
  50. Spiotto MT, Chung TD(2000a)STAT3 mediates IL-6-induced growth inhibition in the human prostate cancer cell line LNCaP. Prostate42: 88–98CrossRefGoogle Scholar
  51. Spiotto MT, Chung TD(2000b)STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells. Prostate42: 186–195CrossRefGoogle Scholar
  52. Steiner H, Godoy-Tundidor S, Rogatsch H, Berger AP, Fuchs D, Comuzzi B, Bartsch G, Hobisch A, Culig Z(2003)Accelerated in vivo growth of prostate tumors that up-regulate interleukin-6 is associated with reduced retinoblastoma protein expression and activation of the mitogen-activated protein kinase pathway. Am J Pathol162: 655–663PubMedCrossRefGoogle Scholar
  53. Steiner H, Berger AP, Godoy-Tundidor S, Bjartell A, Lilja H, Bartsch G, Hobisch A, Culig Z(2004)Vascular endothelial growth factor autocrine loop is established in prostate cancer cells generated after prolonged treatment with interleukin-6. Eur J Cancer40: 1066–1072PubMedCrossRefGoogle Scholar
  54. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL(2005)Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res11: 4653–4657PubMedCrossRefGoogle Scholar
  55. Tong M, Tai HH(2004)Synergistic induction of the nicotinamide adenine dinucleotide-linked 15-hydroxyprostaglandin dehydrogenase by an androgen and interleukin-6 or forskolin in human prostate cancer cells. Endocrinology145: 2141–2147PubMedCrossRefGoogle Scholar
  56. Twillie DA, Eisenberger MA, Carducci MA, Hseih W-S, Kim WY, Simons JW(1995)Interleukin-6: a candidate mediator of human prostate cancer morbidity. Urology45: 542–549PubMedCrossRefGoogle Scholar
  57. Ueda T, Bruchovsky N, Sadar MD(2002a)Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. J Biol Chem277: 7076–7085CrossRefGoogle Scholar
  58. Ueda T, Mawji NR, Bruchovsky N, Sadar MD(2002b)Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells. J Biol Chem277: 38087–38094CrossRefGoogle Scholar
  59. Wallner L, Dai J, Escara-Wilke J, Zhang J, Yao Z, Lu Y, Trikha M, Nemeth JA, Zaki MH, Keller ET(2006)Inhibition of interleukin-6 with CNTO328, an anti-interleukin-6 monoclonal antibody, inhibits conversion of androgen-dependent prostate cancer to an androgen-independent phenotype in orchiectomized mice. Cancer Res66: 3087–3095PubMedCrossRefGoogle Scholar
  60. Wang G, Jones SJ, Marra MA, Sadar MD(2006)Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene25: 7311–7323PubMedCrossRefGoogle Scholar
  61. Wang Q, Horiatis D, Pinski J(2004)Interleukin-6 inhibits the growth of prostate cancer xenografts in mice by the process of neuroendocrine differentiation. Int J Cancer111: 508–513PubMedCrossRefGoogle Scholar
  62. Weber A, Hengge UR, Bardenhauer W, Tischoff I, Sommerer F, Markwarth A, Dietz A, Wittekind C, Tannapfel A(2005)SOCS-3 is frequently methylated in head and squamous cell carcinoma and its precursor lesions and causes growth inhibition. Oncogene24: 6699–6708PubMedCrossRefGoogle Scholar
  63. Yang L, Wang L, Lin HK, Kan PY, Xie S, Tsai M, Wang PH, Chen YT, Chang C(2003)Interleukin-6 differentially regulates androgen receptor transactivation via PI3K-Akt, STAT3, and MAPK, three distinct signal pathways in prostate cancer cells. Biochem Biophys Res Commun305: 462–469PubMedCrossRefGoogle Scholar
  64. Yeh S, Lin HK, Kang HY, Thin TH, Lin MF, Chang C(1999)From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells. Proc Natl Acad Sci USA96: 5458–5463PubMedCrossRefGoogle Scholar
  65. Zegarra-Moro OL, Schmidt LJ, Huang H, Tindall DJ(2002)Disruption of androgen receptor function inhibits proliferation of androgen-refractory prostate cancer cells. Cancer Res62: 1008–1013PubMedGoogle Scholar
  66. Zerbini LF, Wang Y, Cho JY, Libermann TA(2003)Constitutive activation of nuclear factor kappaB p50/p65 and Fra-1 and JunD is essential for deregulated interleukin 6 expression in prostate cancer. Cancer Res63: 2206–2215PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of UrologyInnsbruck Medical UniversityInnsbruckAustria

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