Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 145 No. 5152 (2015)

IL-6/STAT3/ARF: the guardians of senescence, cancer progression and metastasis in prostate cancer

  • Jan Pencik
  • Robert Wiebringhaus
  • Martin Susani
  • Zoran Culig
  • Lukas Kenner
DOI
https://doi.org/10.4414/smw.2015.14215
Cite this as:
Swiss Med Wkly. 2015;145:w14215
Published
13.12.2015

Summary

Prostate cancer is one of the most prevalent forms of cancer in men worldwide. It remains a clinical challenge to identify lethal metastatic prostate cancers, which escape standard therapeutic intervention. Aberrant interleukin-6 (IL-6) / signal transducer and activator of transcription-3 (STAT3) signalling and loss of p53 occur during prostate cancer progression to metastatic disease. The abnormality of the IL-6/STAT3/p53 axis is frequently accompanied by other genetic alterations; however, its potential role as an important mediator of oncogenic reprogramming, invasion and metastatic transformation remains unknown. The failure of anti-IL-6 treatments is still unexplained and may be due to an incomplete understanding of the mechanism of the in vivo role of IL-6/STAT3 in prostate cancer. The identification of the alternative reading frame protein (ARF) / murine double minute protein (MDM2) / p53 tumour suppressor pathway potentially involving the IL-6/STAT3 axis as a restricting factor in prostate cancer deficient in the tumour suppressor phosphatase and tensin homologue (PTEN) opened new avenues to currently available therapies. This review summarises the current knowledge on the role of crucial pathways driving prostate cancer progression as well as metastatic disease and discusses the potential use of novel specific target molecules and how it can be exploited to avoid overtreatment and increase quality of life.

References

  1. Schaper F, Rose-John S. Interleukin-6: Biology, signaling and strategies of blockade. Cytokine Growth Factor Rev. 2015;26(5):475–87.
  2. Hobisch A, Rogatsch H, Hittmair A, Fuchs D, Bartsch G, Jr., Klocker H, et al. Immunohistochemical localization of interleukin-6 and its receptor in benign, premalignant and malignant prostate tissue. J Pathol. 2000;191:239–44.
  3. 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.
  4. Twillie DA, Eisenberger MA, Carducci MA, Hseih WS, Kim WY, Simons JW. Interleukin-6: a candidate mediator of human prostate cancer morbidity. Urology. 1995;45:542–9.
  5. Keller ET, Chang C, Ershler WB. Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter. J Biol Chem. 1996;271:26267–75.
  6. Nadiminty N, Lou W, Sun M, Chen J, Yue J, Kung HJ, et al. Aberrant activation of the androgen receptor by NF-kappaB2/p52 in prostate cancer cells. Cancer Res. 2010;70:3309–19.
  7. Giri D, Ozen M, Ittmann M. Interleukin-6 is an autocrine growth factor in human prostate cancer. Am J Pathol. 2001;159:2159–65.
  8. Park JI, Lee MG, Cho K, Park BJ, Chae KS, Byun DS, et al. Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways. Oncogene. 2003;22:4314–32.
  9. Culig Z, Steiner H, Bartsch G, Hobisch A. Interleukin-6 regulation of prostate cancer cell growth. J Cell Biochem. 2005;95:497–505.
  10. Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest. 2007;117:3988–4002.
  11. Shalapour S, Font-Burgada J, Di Caro G, Zhong Z, Sanchez-Lopez E, et al. Immunosupressive plasma cells impede T-Cell dependent immunogenic chemotherapy. Nature 2015;521(7550):94–8.
  12. Degeorges A, Tatoud R, Fauvel-Lafeve F, Podgorniak MP, Millot G, de Cremoux P, Calvo F. Stromal cells from human benign prostate hyperplasia produce a growth-inhibitory factor for LNCaP prostate cancer cells, identified as interleukin-6. Int J Cancer. 1996;68:207–14.
  13. Chung TD, Yu JJ, Kong TA, Spiotto MT, Lin JM. Interleukin-6 activates phosphatidylinositol-3 kinase, which inhibits apoptosis in human prostate cancer cell lines. Prostate. 2000;42:1–7.
  14. Mori S, Murakami-Mori K, Bonavida B. 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. 1999;257:609–14.
  15. Wang Q, Horiatis D, Pinski J. Interleukin-6 inhibits the growth of prostate cancer xenografts in mice by the process of neuroendocrine differentiation. Int J Cancer. 2004;111:508–13.
  16. Grabner B, Schramek D, Mueller KM, Moll HP, Svinka J, Hoffmann T, et al. Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis. Nat Commun. 2015;6:6285.
  17. McFarland BC, Gray GK, Nozell SE, Hong SW, Benveniste EN. Activation of the NF-kappaB pathway by the STAT3 inhibitor JSI-124 in human glioblastoma cells. Mol Cancer Res. 2013;11:494–505.
  18. Ni Z, Lou W, Leman ES, Gao AC. Inhibition of constitutively activated Stat3 signaling pathway suppresses growth of prostate cancer cells. Cancer Res. 2000;60:1225–8.
  19. Qiu Y, Ravi L, Kung HJ. Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells. Nature. 1998;393:83–5.
  20. Shiota M, Bishop JL, Nip KM, Zardan A, Takeuchi A, Cordonnier T, et al. Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer. Cancer Res. 2013;73:3109–19.
  21. Cavarretta IT, Neuwirt H, Untergasser G, Moser PL, Zaki MH, Steiner H, et al. The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1. Oncogene. 2007;26:2822–32.
  22. Santer FR, Malinowska K, Culig Z, Cavarretta IT. Interleukin-6 trans-signalling differentially regulates proliferation, migration, adhesion and maspin expression in human prostate cancer cells. Endocr Relat Cancer. 2010;17:241–53.
  23. Rojas A, Liu G, Coleman I, Nelson PS, Zhang M, Dash R, et al. IL-6 promotes prostate tumorigenesis and progression through autocrine cross-activation of IGF-IR. Oncogene. 2011;30:2345–55.
  24. Steiner H, Berger AP, Godoy-Tundidor S, Bjartell A, Lilja H, Bartsch G, et al. An autocrine loop for vascular endothelial growth factor is established in prostate cancer cells generated after prolonged treatment with interleukin 6. Eur J Cancer. 2004;40:1066–72.
  25. Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao J, et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell. 2003;4:209–21.
  26. Pencik J, Schlederer M, Gruber W, Unger C, Walker SM, Chalaris A, et al. STAT3 regulated ARF expression suppresses prostate cancer metastasis. Nat Commun. 2015;6:7736.
  27. Toso A, Revandkar A, Di Mitri D, Guccini I, Proietti M, Sarti M, et al. Enhancing chemotherapy efficacy in pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 2014;9:75–89.
  28. Alonzi T, Maritano D, Gorgoni B, Rizzuto G, Libert C, Poli V. Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene inactivation [correction of activation] in the liver. Mol Cell Biol. 2001;21:1621–32.
  29. Akira S. Roles of STAT3 defined by tissue-specific gene targeting. Oncogene. 2000;19:2607–11.
  30. Takeda K, Kaisho T, Yoshida N, Takeda J, Kishimoto T, Akira S. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J Immunol. 1998;161:4652–60.
  31. Yang J, Chatterjee-Kishore M, Staugaitis SM, Nguyen H, Schlessinger K, Levy DE, et al. Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res. 2005;65:939–47.
  32. Yang J, Stark GR. Roles of unphosphorylated STATs in signaling. Cell Res. 2008;18:443–51.
  33. Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner C, Levy DE. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science. 2009;324:1713–6.
  34. Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, et al. Function of mitochondrial Stat3 in cellular respiration. Science. 2009;323:793–7.
  35. Lan L, Holland JD, Qi J, Grosskopf S, Vogel R, Gyorffy B, et al. Shp2 signaling suppresses senescence in PyMT-induced mammary gland cancer in mice. EMBO J. 2015;34:1493–508.
  36. Ding Z, Wu CJ, Chu GC, Xiao Y, Ho D, Zhang J, et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature. 2011;470:269–73.
  37. Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 2005;436:725–30.
  38. Ding Z, Wu CJ, Jaskelioff M, Ivanova E, Kost-Alimova M, Protopopov A, et al. Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases. Cell. 2012;148:896–907.
  39. Lin D, Wyatt AW, Xue H, Wang Y, Dong X, Haegert A, et al. High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development. Cancer Res. 2014;74:1272–83.
  40. Russell PJ, Russell P, Rudduck C, Tse BW, Williams ED, Raghavan D. Establishing prostate cancer patient derived xenografts: lessons learned from older studies. Prostate. 2015;75:628–36.
  41. Chua CW, Shibata M, Lei M, Toivanen R, Barlow LJ, Bergren SK, et al. Single luminal epithelial progenitors can generate prostate organoids in culture. Nat Cell Biol. 2014;16:951–61, 951–4.
  42. Gao D, Vela I, Sboner A, Iaquinta PJ, Karthaus WR, Gopalan A, et al. Organoid cultures derived from patients with advanced prostate cancer. Cell. 2014;159:176–87.
  43. Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat JP, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012;44:685–9.
  44. Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487:239–43.
  45. Ahmad I, Patel R, Singh LB, Nixon C, Seywright M, Barnetson RJ, et al. HER2 overcomes PTEN (loss)-induced senescence to cause aggressive prostate cancer. Proc Natl Acad Sci U S A. 2011);108:16392–7.
  46. Chen Y, Chi P, Rockowitz S, Iaquinta PJ, Shamu T, Shukla S, et al. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nat Med. 2013;19:1023–9.
  47. Hobisch A, Culig Z, Radmayr C, Bartsch G, Klocker H, Hittmair A. Distant metastases from prostatic carcinoma express androgen receptor protein. Cancer Res. 1995;55:3068–72.
  48. Chang GS, Chen XA, Park B, Rhee HS, Li P, Han KH, et al. A comprehensive and high-resolution genome-wide response of p53 to stress. Cell Rep. 2014;8:514–27.
  49. Delk NA, Farach-Carson MC. Interleukin-6: a bone marrow stromal cell paracrine signal that induces neuroendocrine differentiation and modulates autophagy in bone metastatic PCa cells. Autophagy. 2012;8:650–63.
  50. Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, D’Amelio M, et al. Regulation of autophagy by cytoplasmic p53. Nat Cell Biol. 2008;10:676–87.
  51. Malinowska K, Neuwirt H, Cavarretta IT, Bektic J, Steiner H, Dietrich H, 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.
  52. Liu C, Lou W, Armstrong C, Zhu Y, Evans CP, Gao AC. (2015). Niclosamide suppresses cell migration and invasion in enzalutamide resistant prostate cancer cells via Stat3-AR axis inhibition. Prostate.
  53. 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.
  54. 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.
  55. Heemers HV, Sebo TJ, Debes JD, Regan KM, Raclaw KA, Murphy LM, et al. Androgen deprivation increases p300 expression in prostate cancer cells. Cancer Res. 2007;67:3422–30.
  56. Kroon P, Berry PA, Stower MJ, Rodrigues G, Mann VM, Simms M, et al. JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells. Cancer Res. 2013;73:5288–98.
  57. Azevedo A, Cunha V, Teixeira AL, Medeiros R. IL-6/IL-6R as a potential key signaling pathway in prostate cancer development. World J Clin Oncol. 2011;2:384–96.
  58. Zaki MH, Nemeth JA, Trikha M. CNTO 328, a monoclonal antibody to IL-6, inhibits human tumor-induced cachexia in nude mice. Int J Cancer. 2004;111:592–5.
  59. Wallner L, Dai J, Escara-Wilke J, Zhang J, Yao Z, Lu Y, et al. 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 Res. 2006;66:3087–95.
  60. Nonn L, Peng L, Feldman D, Peehl DM. Inhibition of p38 by vitamin D reduces interleukin-6 production in normal prostate cells via mitogen-activated protein kinase phosphatase 5: implications for prostate cancer prevention by vitamin D. Cancer Res. 2006;66:4516–24.
  61. 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.
  62. Dorff TB, Goldman B, Pinski JK, Mack PC, Lara PN, Jr., Van Veldhuizen PJ, Jr., et al. Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-pretreated patients with castration-resistant prostate cancer. Clin Cancer Res. 2010;16:3028–34.
  63. Fizazi K, De Bono JS, Flechon A, Heidenreich A, Voog E, Davis NB, et al. Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. Eur J Cancer. 2012;48:85–93.
  64. Ando M, Uehara I, Kogure K, Asano Y, Nakajima W, Abe Y, et al. Interleukin 6 enhances glycolysis through expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3. J Nippon Med Sch. 2010;77:97–105.
  65. Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, et al. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell. 2013;24:213–28.
  66. Wolf A, Agnihotri S, Micallef J, Mukherjee J, Sabha N, Cairns R, et al. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J Exp Med. 2011;208:313–26.
  67. Cardaci S, Desideri E, Ciriolo MR. Targeting aerobic glycolysis: 3-bromopyruvate as a promising anticancer drug. J Bioenerg Biomembr. 2012;44:17–29.
  68. Kato H, Sekine Y, Furuya Y, Miyazawa Y, Koike H, Suzuki K. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor. Biochem Biophys Res Commun. 2015;461:115–21.
  69. Wang L, Xiong H, Wu F, Zhang Y, Wang J, Zhao L, et al. Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth. Cell Rep. 2014;8:1461–74.