Skip to main content
SpringerLink
Log in

Androgen-Independent Induction of Androgen-Responsive Genes by Interleukin-6 Regulation

  • Chapter
  • First Online:
Androgen-Responsive Genes in Prostate Cancer

  • 919 Accesses

Abstract

Androgen receptor (AR) is expressed in recurrent prostate cancer and its increased activation could be a consequence of protein stabilization, point mutations, and interaction with nonsteroidal compounds. One of the molecules which activate the androgen receptor in a ligand-independent and synergistic manner is the proinflammatory cytokine interleukin-6 (IL-6). IL-6 regulates prostate growth in an autocrine and paracrine manner. AR activation by IL-6 has different consequences for LNCaP and MDA PCa 2b cells. Whereas LNCaP cells are inhibited by IL-6, in vitro and in vivo growth of MDA PCa 2b cells is enhanced by the cytokine. AR activation by IL-6 is mediated by coactivators p300 and SRC-1 which are both expressed in prostate cancer tissues. Recent studies on suppressors of cytokine signaling and protein inhibitors of activated STAT revealed that there are several complex interactions between the pathways of IL-6 and androgen. Suppressor of cytokine signaling-3 is upregulated by IL-6 and response to androgenic hormones. The IL-6/AR axis is a target for novel therapies in prostate cancer. The monoclonal anti-IL-6 antibody siltuximab could delay progression of an androgen-sensitive xenograft. However, in clinical studies siltuximab was used mostly in the late stage disease in which it did not show clinical activity as a monotherapy.

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 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
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

  1. Van der Kwast TH, Schalken J, Ruizeveld de Vinter JA, van Vroonhoven CC, Mulder E, Boersma W, Trapman J (1991) Androgen receptors in endocrine therapy-resistant human prostate cancer. Int J Cancer 48:188–193

    Google Scholar 

  2. Hobisch A, Culig Z, Radmayr C, Bartsch G, Klocker H, Hittmair A (2005) Distant metastases from prostatic carcinoma express androgen receptor protein. Cancer Res 55:3068–3072

    Google Scholar 

  3. Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinänen R, Palmberg C, Palotie A, Tammela T, Isola J, Kallioniemi OP (1995) In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 9:401–406

    Article  PubMed  CAS  Google Scholar 

  4. Attard G, Richards J, de Bono JS (2011) New strategies in metastatic prostate cancer: targeting the androgen receptor signaling pathway. Clin Cancer Res 17:1649–1657

    Article  PubMed  CAS  Google Scholar 

  5. Mukherji D, Pezaro CJ, De Bono JS (2012) MDV3100 for the treatment of prostate cancer. Expert Opin Invest Drugs 21:227–233

    Article  CAS  Google Scholar 

  6. Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N, Kusaka M, Miyamoto M (2003) Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res 63:149–153

    PubMed  CAS  Google Scholar 

  7. Veldscholte J, Ris-Stalpers C, Kuiper GG, Jenster G, Berrevoets C, Claassen E, van Roij HC, Trapman J, Brinkmann AO, Mulder E (1990) A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun 173:534–540

    Article  PubMed  CAS  Google Scholar 

  8. Wagner KU, Schmidt JW (2011) The two faces of Janus kinases and their respective STATs in mammary gland development and cancer. J Carcinog 10(32):2011

    Google Scholar 

  9. Gioeli D, Mandell JW, Petroni GR, Frierson HF Jr, Weber MJ (1999) Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res 59:279–284

    PubMed  CAS  Google Scholar 

  10. Kreisberg JI, Malik SN, Prihoda TJ, Bedolla RG, Troyer DA, Kreisberg S, Ghosh PM (2004) Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res 64:5232–5236

    Article  PubMed  CAS  Google Scholar 

  11. Santer FR, Malinowska K, Culig Z, Cavarretta IT (2010) Interleukin-6 trans-signaling differentially regulates proliferation, migration, adhesion and maspin expression in human prostate cancer cells. Endocr Relat Cancer 17:241–253

    Article  PubMed  CAS  Google Scholar 

  12. Sfanos KS, De Marzo AM (2012) Prostate cancer and inflammation: the evidence. Histopathology 60:199–215

    Article  PubMed  Google Scholar 

  13. 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, keratinocyte growth factor, and epidermal growth factor. Cancer Res 54:5474–5478

    PubMed  CAS  Google Scholar 

  14. Nazareth LV, Weigel NL (1996) Activation of the human androgen receptor through a protein kinase A signaling pathway. J Biol Chem 271:19900–19907

    Article  PubMed  CAS  Google Scholar 

  15. 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 Med 5:280–285

    Article  PubMed  CAS  Google Scholar 

  16. 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 for induction of androgen target genes through MAP kinase in prostate cancer cells. Proc Natl Acad Sci USA 96:5458–5463

    Article  PubMed  CAS  Google Scholar 

  17. Wang G, Jones SJ, Marra MA, Sadar MD (2006) Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogenes 25:7311–7323

    Article  CAS  Google Scholar 

  18. 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 Res 66:10449–10459

    Article  PubMed  CAS  Google Scholar 

  19. 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 Res 58:4640–4645

    PubMed  CAS  Google Scholar 

  20. Sartorius CA, Tung L, Takimoto GS, Horwitz KB (1993) Antagonist-occupied human progesterone receptors blund to DNA are functionally switched to transcriptional agonists by cAMP. J Biol Chem 268:9262–9266

    PubMed  CAS  Google Scholar 

  21. Twillie DA, Eisenberger MA, Caarducci MA, Hseih WS, Kim WY, Simons JW (1995) Interleukin-6: a candidate mediator of human prostate cancer morbidity. Urology 45:542–549

    Article  PubMed  CAS  Google Scholar 

  22. Keller ET, Chang C, Ershler WB (1996) Inhibition of NF kappa B activity through maintenance of IkapaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter. J Biol Chem 271:26267–26275

    Article  PubMed  CAS  Google Scholar 

  23. Hobisch A, Rogatsch H, Hittmair A, Fuchs D, Bartsch G Jr, Klocker H, Bartsch G, Culig Z (2000) Immunohistochemical localization of interleukin-6 and its receptor in benign, premalignant and malignant prostate tissue. J Pathol 191:239–244

    Article  PubMed  CAS  Google Scholar 

  24. 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 (IL-6) treatment express IL-6 and acquire an IL-6 partially resistant phenotype. Clin Cancer Res 7:2941–2948

    PubMed  CAS  Google Scholar 

  25. Sadar MD, Gleave ME (2000) Ligand-independent activation of the androgen receptor by the differentiation agent butyrate in human prostate cancer cells. Cancer Res 60:5825–5831

    PubMed  CAS  Google Scholar 

  26. Kim O, Jiang T, Xie Y, Guo Z, Chen H, Qiu Y (2004) Synergism of cytoplasmic kinases in IL-6-induced ligand-independent activation of androgen receptor in prostate cancer cells. Oncogene 23:1838–1884

    Article  PubMed  CAS  Google Scholar 

  27. Giri D, Ozen M, Ittmann M (2001) Interleukin-6 is an autocrine growth factor in human prostate cancer. Am J Pathol 159:2159–2165

    Article  PubMed  CAS  Google Scholar 

  28. Malinowska K, Neuwirt H, Cavarretta IT, Bektic J, Steiner H, Dietrich H, Moser PL, Fuchs D, Hobisch A, Culig Z (2009) Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor. Endocr Relat Cancer 16:155–169

    Article  PubMed  CAS  Google Scholar 

  29. Mori S, Murakami-Mori K, Bonavida B (1999) Interleukin-6 induces G1 arrest through induction of p27 (Kip1), a cyclin-dependent kinase inhibitor, and neuron-like morphology in LNCaP prostate tumor cells. Biochem Biophys Res Commun 257:609–614

    Article  PubMed  CAS  Google Scholar 

  30. Heemers HV, Sebo TJ, Debes JD, Regan KM, Raclaw KA, Murphy LM, Culig Z, Hobisch A, Tindall DJ (2007) Androgen deprivation increases p300 expression in prostate cancer cells. Cancer Res 67:3422–3430

    Article  PubMed  CAS  Google Scholar 

  31. Debes JD, Schmidt LJ, Huang H, Tindall DJ (2005) p300 mediates androgen-independent transactivation of the androgen receptor by interleukin 6. Cancer Res 62:5632–5636

    Google Scholar 

  32. 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 Res 65:5965–5973

    Article  PubMed  CAS  Google Scholar 

  33. Santer FR, Höschele PP, Oh SJ, Erb HH, Bouchal J, Cavarretta IT, Parson W, Meyers DJ, Cole PA, Culig Z (2011) Inhibition of the acetyltransferases p300 and CBP reveals a targetable function for p300 in the survival and invasion pathways of prostate cancer cell lines. Mol Cancer Ther 10:1644–1655

    Article  PubMed  CAS  Google Scholar 

  34. Agoulnik IU, Vaid A, Bingman WE 3rd, Erdeme H, Frolov A, Smith CL, Ayala G, Ittmann MM, Weigel NL (2005) Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression. Cancer Res 65:7959–7967

    PubMed  CAS  Google Scholar 

  35. Debes JD, Schmidt Lj, Huang H, Tindall D (2002) p300 Mediates androgen-independent transactivation of the androgen receptor by interleukin-6. Cancer Res 62:5632–5636

    Google Scholar 

  36. Ueda T, Mawji NR, Bruchowsky N, Sadar MD (2002) Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in porstate cancer cells. J Biol Chem 277:38087–38094

    Article  PubMed  CAS  Google Scholar 

  37. Puhr M, Santer FR, Neuwirt H, Susani M, Nemeth JA, Hobisch A, Kenner L, Culig Z (2009) Down-regulation of suppressor of cytokine signaling-3 causes prostate cancer cell death through activation of the extrinsic and intrinsich apoptosis pathways. Cancer Res 69:7375–7384

    Article  PubMed  CAS  Google Scholar 

  38. 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 Cancer 14:1007–1019

    Article  PubMed  CAS  Google Scholar 

  39. Neuwirt H, Puhr M, Santer FR, Susani M, Doppler W, Marcias G, Rauch V, Brugger M, Hobisch A, Kenner L, Culig Z (2009) Suppressor of cytokine signaling (SOCS)-1 is expressed in human prostate cancer and exerts growth-inhibitory function through down-regulation of cyclins and cyclin-dependent kinases. Am J Pathol 174:1921–1930

    Article  PubMed  CAS  Google Scholar 

  40. Gross M, Liu B, Tan J, French FS, Carey M, Shuai K (2001) Distinct effects of PIAS proteins on androgen-mediated gene activation in prostate cancer cells. Oncogene 20:3880–3887

    Article  PubMed  CAS  Google Scholar 

  41. Hoefer J, Schäfer G, Klocker H, Erb HH, Mills IG, Hengst L, Puhr M, Culig Z (2012) PIAS1 is increased in human prostate cancer and enhances proliferation through inhibition of p21. Am J Pathol 180:2097–2107

    Article  PubMed  CAS  Google Scholar 

  42. Smith PC, Keller ET (2001) Anti-interleukin-6 monoclonal antibody induces regression of human prostate cancer xenografts in nude mice. Prostate 48:47–53

    Article  PubMed  CAS  Google Scholar 

  43. 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 ainti-interleukin-6 monoclonal antibody, inhibits conversion of androgen-dependent to an androgen-independent phenotype in orchiectomized mice. Cancer Res 66:3087–3095

    Article  PubMed  CAS  Google Scholar 

  44. Comuzzi B, Nemes C, Schmidt S, Jasarevic Z, Lodde M, Pycha A, Batsch 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 Pathol 204:159–166

    Article  PubMed  CAS  Google Scholar 

  45. Karkera J, Steiner H, Li W, Skradski V, Moser PL, Riethdorf S, Reddy M, Puchalski T, Safer K, Prabhakar U, Pantel K, Qi M, Culig Z (2011) The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study. Prostate 71:1455–1465

    Article  PubMed  CAS  Google Scholar 

  46. Dorff TB, Goldman B, Pinski JK, Mack PC, Lara JRPN, van Veldhuizen Jr PJ, Quinn JI, Vogelzang NJ, Thompson IM Jr, Hussain MH (2010) Clinical and correlative results of SWOG 50354: a phase II trial of CNTO328 siltuximab, a monoclonal antibody against IL-6, in patients with castration-resistant prostate cancer. Clin Cancer Res 16:3028–3034

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    Zoran Culig

Authors
  1. Zoran Culig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zoran Culig .

Editor information

Editors and Affiliations

  1. , Shadyside Medical Center, University of Pittsburgh, Centre Ave 5200, Pittsburgh, 15232, Pennsylvania, USA

    Zhou Wang

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Culig, Z. (2013). Androgen-Independent Induction of Androgen-Responsive Genes by Interleukin-6 Regulation. In: Wang, Z. (eds) Androgen-Responsive Genes in Prostate Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6182-1_11

Download citation

Publish with us

Policies and ethics

Search

Navigation