Skip to main content
SpringerLink
Log in

Role of IL-6 in Regulating the Androgen Receptor

  • Chapter
  • First Online:
Androgen Action in Prostate Cancer

  • 837 Accesses

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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: 7959–7967

    PubMed  CAS  Google Scholar 

  • 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: 106–109

    Article  PubMed  CAS  Google Scholar 

  • 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: 2199–2208

    Article  PubMed  CAS  Google Scholar 

  • 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: 2886–2895

    Article  PubMed  CAS  Google Scholar 

  • 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: 1860–1869

    Article  Google Scholar 

  • 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: 25–32

    Article  PubMed  CAS  Google Scholar 

  • 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: 33–39

    Article  PubMed  Google Scholar 

  • 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: 159–166

    Article  PubMed  CAS  Google Scholar 

  • 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: 280–285

    Article  PubMed  CAS  Google Scholar 

  • 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: 5474–5478

    PubMed  CAS  Google Scholar 

  • Culig Z, Steiner H, Bartsch G, Hobisch A(2005)Interleukin-6 regulation of prostate cancer cell growth. J Cell Biochem95: 497–505

    Article  PubMed  CAS  Google Scholar 

  • 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: 256–269

    Article  PubMed  CAS  Google Scholar 

  • Debes JD, Schmidt LJ, Huang H, Tindall DJ(2002)p300 mediates interleukin-6-dependent transactivation of the androgen receptor. Cancer Res62: 5632–5636

    PubMed  CAS  Google Scholar 

  • Debes JD, Sebo TJ, Lohse CM, Murphy LM, Haugen de AL, Tindall DJ(2003)p300 in prostate cancer proliferation and progression. Cancer Res63: 7638–7640

    PubMed  CAS  Google Scholar 

  • 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: 5965–5973

    Article  PubMed  CAS  Google Scholar 

  • 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: 207–214

    Article  PubMed  CAS  Google Scholar 

  • 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: 10449–10459

    Article  PubMed  CAS  Google Scholar 

  • 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: 997–1007

    Article  PubMed  CAS  Google Scholar 

  • 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: 8460–8464

    Article  PubMed  CAS  Google Scholar 

  • 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: 1815–1820

    Article  PubMed  CAS  Google Scholar 

  • Giri D, Ozen M, Ittmann M(2001)Interleukin-6 is an autocrine growth factor in human prostate cancer. Am J Pathol159: 2159–2165

    Article  PubMed  CAS  Google Scholar 

  • 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: 2356–2361

    PubMed  CAS  Google Scholar 

  • 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: 3727–3738

    Article  PubMed  CAS  Google Scholar 

  • 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: 14133–14138

    Article  PubMed  CAS  Google Scholar 

  • 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: 4640–4645

    PubMed  CAS  Google Scholar 

  • 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: 239–244

    Article  PubMed  CAS  Google Scholar 

  • 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: 2941–2948

    PubMed  CAS  Google Scholar 

  • 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: 385–392

    PubMed  CAS  Google Scholar 

  • Jia L, Choong CS, Ricciardelli C, Kim J, Tilley WD, Coetzee GA(2004)Androgen receptor signaling: mechanism of interleukin-6 inhibition. Cancer Res64: 2619–2626

    Article  PubMed  CAS  Google Scholar 

  • 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: 1838–1844

    Article  PubMed  CAS  Google Scholar 

  • 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: 6037–6044

    CAS  Google Scholar 

  • 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: 764–773

    Article  PubMed  CAS  Google Scholar 

  • 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: 1773–1781

    PubMed  CAS  Google Scholar 

  • 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: 50902–50907

    Article  Google Scholar 

  • 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: 179–187

    Article  PubMed  CAS  Google Scholar 

  • 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: 6659–6666

    PubMed  CAS  Google Scholar 

  • 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: 1011–1015

    PubMed  CAS  Google Scholar 

  • 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: 2702–2706

    PubMed  CAS  Google Scholar 

  • Nazareth LV, Weigel NL(1996)Activation of the human androgen receptor through a protein kinase A signaling pathway. J Biol Chem271: 19900–19907

    Article  PubMed  CAS  Google Scholar 

  • 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: 1007–1019

    Article  PubMed  CAS  Google Scholar 

  • 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: 6406–6417

    PubMed  CAS  Google Scholar 

  • 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: 141–146

    PubMed  CAS  Google Scholar 

  • 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: 4314–4332

    Article  PubMed  CAS  Google Scholar 

  • 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: 41–49

    Article  PubMed  CAS  Google Scholar 

  • Sadar MD, Gleave ME(2000)Ligand-independent activation of the androgen receptor by the differentiation agent butyrate in human prostate cancer cells. Cancer Res60: 5825–5831

    PubMed  CAS  Google Scholar 

  • 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: 7605–7609

    Article  PubMed  CAS  Google Scholar 

  • 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: 9262–9266

    PubMed  CAS  Google Scholar 

  • 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: 1008–1015

    Article  PubMed  CAS  Google Scholar 

  • Smith PC, Keller ET(2001)Anti-interleukin-6 monoclonal antibody induces regression of human prostate cancer xenografts in nude mice. Prostate48: 47–53

    Article  PubMed  CAS  Google Scholar 

  • Spiotto MT, Chung TD(2000a)STAT3 mediates IL-6-induced growth inhibition in the human prostate cancer cell line LNCaP. Prostate42: 88–98

    Article  CAS  Google Scholar 

  • Spiotto MT, Chung TD(2000b)STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells. Prostate42: 186–195

    Article  CAS  Google Scholar 

  • 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: 655–663

    Article  PubMed  CAS  Google Scholar 

  • 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: 1066–1072

    Article  PubMed  CAS  Google Scholar 

  • Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL(2005)Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res11: 4653–4657

    Article  PubMed  CAS  Google Scholar 

  • 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: 2141–2147

    Article  PubMed  CAS  Google Scholar 

  • 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: 542–549

    Article  PubMed  CAS  Google Scholar 

  • 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: 7076–7085

    Article  CAS  Google Scholar 

  • 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: 38087–38094

    Article  CAS  Google Scholar 

  • 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: 3087–3095

    Article  PubMed  CAS  Google Scholar 

  • 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: 7311–7323

    Article  PubMed  CAS  Google Scholar 

  • 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: 508–513

    Article  PubMed  CAS  Google Scholar 

  • 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: 6699–6708

    Article  PubMed  CAS  Google Scholar 

  • 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: 462–469

    Article  PubMed  CAS  Google Scholar 

  • 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: 5458–5463

    Article  PubMed  CAS  Google Scholar 

  • 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: 1008–1013

    PubMed  CAS  Google Scholar 

  • 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: 2206–2215

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020, Innsbruck, Austria

    Zoran Culig

Authors
  1. Zoran Culig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alfred Hobisch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zoran Culig .

Editor information

James Mohler Donald Tindall

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Culig, Z., Hobisch, A. (2009). Role of IL-6 in Regulating the Androgen Receptor. In: Mohler, J., Tindall, D. (eds) Androgen Action in Prostate Cancer. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69179-4_20

Download citation

Publish with us

Policies and ethics

Search

Navigation