Skip to main content

Role of interleukin-6 in cancer progression and therapeutic resistance

Tumor Biology volume 37, pages 11553–11572 (2016)Cite this article

Abstract

In the last several decades, the number of people dying from cancer-related deaths has not reduced significantly despite phenomenal advances in the technologies related to diagnosis and therapeutic modalities. The principal cause behind limitations in the curability of this disease is the reducing sensitivity of the cancer cells towards conventional anticancer therapeutic modalities, particularly in advance stages of the disease. Amongst several reasons, certain secretory factors released by the tumour cells into the microenvironment have been found to confer resistance towards chemo- and radiotherapy, besides promoting growth. Interleukin-6 (IL-6), one of the major cytokines in the tumour microenvironment, is an important factor which is found at high concentrations and known to be deregulated in cancer. Its overexpression has been reported in almost all types of tumours. The strong association between inflammation and cancer is reflected by the high IL-6 levels in the tumour microenvironment, where it promotes tumorigenesis by regulating all hallmarks of cancer and multiple signalling pathways, including apoptosis, survival, proliferation, angiogenesis, invasiveness and metastasis, and, most importantly, the metabolism. Moreover, IL-6 protects the cancer cells from therapy-induced DNA damage, oxidative stress and apoptosis by facilitating the repair and induction of countersignalling (antioxidant and anti-apoptotic/pro-survival) pathways. Therefore, blocking IL-6 or inhibiting its associated signalling independently or in combination with conventional anticancer therapies could be a potential therapeutic strategy for the treatment of cancers with IL-6-dominated signalling.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. Bromberg J, Wang TC. Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell. 2009;15:79–80.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. Grivennikov S, Karin M. Autocrine IL-6 signaling: a key event in tumorigenesis? Cancer Cell. 2008;13:7–9.

    CAS  PubMed  Article  Google Scholar 

  3. Waldner MJ, Foersch S, Neurath MF. Interleukin-6—a key regulator of colorectal cancer development. Int J Biol Sci. 2012;8(9):1248–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Dethlefsen C, Højfeldt G, Hojman P. The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Res Treat. 2013;138(3):657–64.

    CAS  PubMed  Article  Google Scholar 

  5. Culig Z, Puhr M. Interleukin-6: a multifunctional targetable cytokine in human prostate cancer. Mol Cell Endocrinol. 2012;360(1–2):52–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Macciò A, Madeddu C. The role of interleukin-6 in the evolution of ovarian cancer: clinical and prognostic implications—a review. J Mol Med. 2013;91:1355–68.

    PubMed  Article  CAS  Google Scholar 

  7. Miura T, Mitsunaga S, Ikeda M, Shimizu S, Ohno I, Takahashi H, et al. Characterization of patients with advanced pancreatic cancer and high serum interleukin-6 levels. Pancreas. 2015;44(5):756–63.

    CAS  PubMed  Article  Google Scholar 

  8. Chang CH, Hsiao CF, Yeh YM, Chang GC, Tsai YH, Chen YM, et al. Circulating interleukin-6 level is a prognostic marker for survival in advanced nonsmall cell lung cancer patients treated with chemotherapy. Int J Cancer. 2013;132(9):1977–85.

    CAS  PubMed  Article  Google Scholar 

  9. Altundag O, Altundag K, Gunduz E. Interleukin-6 and C-reactive protein in metastatic renal cell carcinoma. J Clin Oncol. 2005;23:1044.

    PubMed  Article  Google Scholar 

  10. Wei LH, Kuo ML, Chen CA, Chou CH, Lai KB, Lee CN, et al. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene. 2003;22:1517–27.

    CAS  PubMed  Article  Google Scholar 

  11. Singh U, Shevra CR, Singh S, Singh N, Kumar S, Rai M. Interleukin-6 and interleukin-4 levels in multiple myeloma and correlation of interleukin-6 with β2 microglobulin and serum creatinine. Clin Cancer Investig J. 2015;4:211–5.

    Article  Google Scholar 

  12. Wu CT, Chen MF, Chen WC, Hsieh CC. The role of IL-6 in the radiation response of prostate cancer. Radiat Oncol. 2013;8:159.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Chen MF, Chen PT, Lu MS, Lin PY, Chen WC, Lee KD. IL-6 expression predicts treatment response and outcome in squamous cell carcinoma of the esophagus. Mol Cancer. 2013;12:26.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. Shibayama O, Yoshiuchi K, Inagaki M, Matsuoka Y, Yoshikawa E, Sugawara Y, et al. Association between adjuvant regional radiotherapy and cognitive function in breast cancer patients treated with conservation therapy. Cancer Med. 2014;3(3):702–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Guo Y, Xu F, Lu T, Duan Z, Zhang Z. Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev. 2012;38(7):904–10.

    CAS  PubMed  Article  Google Scholar 

  16. Veuger SJ, Hunter JE, Durkacz BW. Ionizing radiation-induced NF-kappaB activation requires PARP-1 function to confer radioresistance. Oncogene. 2009;28:832–42.

    CAS  PubMed  Article  Google Scholar 

  17. Kozakai N, Kikuchi E, Hasegawa M, Suzuki E, Ide H, Miyajima A, et al. Enhancement of radiosensitivity by a unique novel NF-kB inhibitor, DHMEQ, in prostate cancer. Br J Cancer. 2012;107:652–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Naugler WE, Karin M. NF-kappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev. 2008;18(1):19–26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Wolf J, Rose-John S, Garbers C. Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine. 2014;70(1):11–20.

    CAS  PubMed  Article  Google Scholar 

  20. Yoon S, Woo SU, Kang JH, Kim K, Shin HJ, Gwak HS, et al. NF-kB and STAT3 cooperatively induce IL6 in starved cancer cells. Oncogene. 2012;31(29):3467–81.

    CAS  PubMed  Article  Google Scholar 

  21. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878–88.

    CAS  PubMed  Article  Google Scholar 

  22. Hirano T, Taga T, Nakano N, Yasukawa K, Kashiwamura S, Shimizu K, et al. Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). Proc Natl Acad Sci U S A. 1985;82(16):5490–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin-6 family of cytokines and gp130. Blood. 1995;86:1243–54.

    CAS  PubMed  Google Scholar 

  24. Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci (Lond). 2012;122(4):143–59.

    CAS  Article  Google Scholar 

  25. Wunderlich FT, Ströhle P, Könner AC, Gruber S, Tovar S, Brönneke HS, et al. Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab. 2010;12(3):237–49.

    CAS  PubMed  Article  Google Scholar 

  26. Taga T, Kishimoto T. Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol. 1997;15:797–819.

    CAS  PubMed  Article  Google Scholar 

  27. Hibi M, Murakami M, Saito M, Hirano T, Taga T, Kishimoto T. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell. 1990;63:1149–57.

    CAS  PubMed  Article  Google Scholar 

  28. Yawata H, Yasukawa K, Natsuka S, Murakami M, Yamasaki K, Hibi M, et al. Structure–function analysis of human IL-6 receptor: dissociation of amino acid residues required for IL-6-binding and for IL-6 signal transduction through gp130. EMBO J. 1993;12(4):1705–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Jones SA, Horiuchi S, Topley N, Yamamoto N, Fuller GM. The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J. 2001;15(1):43–58.

    CAS  PubMed  Article  Google Scholar 

  30. Yoshida K, Taga T, Saito M, Suematsu S, Kumanogoh A, Tanaka T, et al. Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proc Natl Acad Sci U S A. 1996;93(1):407–11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest. 2011;121:3375–83.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Chalaris A, Garbers C, Rabe B, Rose-John S, Scheller J. The soluble interleukin 6 receptor: generation and role in inflammation and cancer. Eur J Cell Biol. 2011;90(6–7):484–94.

    CAS  PubMed  Article  Google Scholar 

  33. Islam O, Gong X, Rose-John S, Heese K. Interleukin-6 and neural stem cells: more than gliogenesis. Mol Biol Cell. 2009;20(1):188–99.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Peters M, Solem F, Goldschmidt J, Schirmacher P, Rose-John S. Interleukin-6 and the soluble interleukin-6 receptor induce stem cell factor and Flt-3L expression in vivo and in vitro. Exp Hematol. 2001;29(2):146–55.

    CAS  PubMed  Article  Google Scholar 

  35. Yeoh GC, Ernst M, Rose-John S, Akhurst B, Payne C, Long S, et al. Opposing roles of gp130-mediated STAT-3 and ERK-1/2 signaling in liver progenitor cell migration and proliferation. Hepatology. 2007;45(2):486–94.

    CAS  PubMed  Article  Google Scholar 

  36. Humphrey RK, Beattie GM, Lopez AD, Bucay N, King CC, Firpo MT, et al. Maintenance of pluripotency in human embryonic stem cells is STAT3 independent. Stem Cells. 2004;22(4):522–30.

    CAS  PubMed  Article  Google Scholar 

  37. Rose-John S. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci. 2012;8(9):1237–47.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. McFarland-Mancini MM, Funk HM, Paluch AM, Zhou M, Giridhar PV, Mercer CA, et al. Differences in wound healing in mice with deficiency of IL-6 versus IL-6 receptor. J Immunol. 2010;184(12):7219–28.

    CAS  PubMed  Article  Google Scholar 

  39. Kovacs E. Investigation of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130) in sera of cancer patients. Biomed Pharmacother. 2001;55(7):391–6.

    CAS  PubMed  Article  Google Scholar 

  40. Jostock T, Müllberg J, Ozbek S, Atreya R, Blinn G, Voltz N, et al. Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur J Biochem. 2001;268(1):160–7.

    CAS  PubMed  Article  Google Scholar 

  41. Akira S, Kishimoto T. IL-6 and NF-IL6 in acute-phase response and viral infection. Immunol Rev. 1992;127:25–50.

    CAS  PubMed  Article  Google Scholar 

  42. Yang R, Lin Q, Gao HB, Zhang P. Stress-related hormone norepinephrine induces interleukin-6 expression in GES-1 cells. Braz J Med Biol Res. 2014;47(2):101–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Zhao W, Liu M, Kirkwood KL. p38alpha stabilizes interleukin-6 mRNA via multiple AU-rich elements. J Biol Chem. 2008;283(4):1778–85.

    CAS  PubMed  Article  Google Scholar 

  44. Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 microRNA, and IL6 links inflammation to cell transformation. Cell. 2009;139(4):693–706.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Narbutt J, Lukamowicz J, Bogaczewicz J, Sysa-Jedrzejowska A, Torzecka JD, Lesiak A. Serum concentration of interleukin-6 is increased both in active and remission stages of pemphigus vulgaris. Mediat Inflamm. 2008;2008:875394.

    Article  CAS  Google Scholar 

  46. D’Auria L, Bonifati C, Mussi A, D’Agosto G, De Simone C, Giacalone B, et al. Cytokines in the sera of patients with pemphigus vulgaris: interleukin-6 and tumour necrosis factor-alpha levels are significantly increased as compared with healthy subjects and correlate with disease activity. Eur Cytokine Netw. 1997;8(4):383–7.

    PubMed  Google Scholar 

  47. Devaraj S, Venugopal SK, Singh U, Jialal I. Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase c-{alpha} and -{beta}. Diabetes. 2005;54(1):85–91.

    CAS  PubMed  Article  Google Scholar 

  48. Blackburn P, Després JP, Lamarche B, Tremblay A, Bergeron J, Lemieux I, et al. Postprandial variations of plasma inflammatory markers in abdominally obese men. Obesity (Silver Spring). 2006;14(10):1747–54.

    CAS  Article  Google Scholar 

  49. Angstwurm MW, Gartner R, Ziegler-Heitbrock HW. Cyclic plasma IL-6 levels during normal menstrual cycle. Cytokine. 1997;9:370–4.

    CAS  PubMed  Article  Google Scholar 

  50. Reihmane D, Dela F. Interleukin-6: possible biological roles during exercise. Eur J Sport Sci. 2014;14(3):242–50.

    PubMed  Article  Google Scholar 

  51. Sakamoto K, Arakawa H, Mita S, Ishiko T, Ikei S, Egami H, et al. Elevation of circulating interleukin 6 after surgery: factors influencing the serum level. Cytokine. 1994;6:181–6.

    CAS  PubMed  Article  Google Scholar 

  52. Keski-Nisula L, Hirvonen MR, Roponen M, Heinonen S, Pekkanen J. Spontaneous and stimulated interleukin-6 and tumor necrosis factor-alpha production at delivery and three months after birth. Eur Cytokine Netw. 2004;15:67–72.

    CAS  PubMed  Google Scholar 

  53. Naffaa M, Makhoul BF, Tobia A, Kaplan M, Aronson D, Saliba W, et al. Interleukin-6 at discharge predicts all-cause mortality in patients with sepsis. Am J Emerg Med. 2013;31(9):1361–4.

    PubMed  Article  Google Scholar 

  54. Muñoz‐Cánoves P, Scheele C, Pedersen BK, Serrano AL. Interleukin‐6 myokine signaling in skeletal muscle: a double‐edged sword? FEBS. 2013;280(17):4131–48.

    Article  CAS  Google Scholar 

  55. Steensberg A, Febbraio MA, Osada T, Schjerling P, van Hall G, Saltin B, et al. Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content. J Physiol. 2001;537:633–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Bastard JP, Maachi M, Van Nhieu JT, Jardel C, Bruckert E, Grimaldi A, et al. Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J Clin Endocrinol Metab. 2002;87(5):2084–9.

    CAS  PubMed  Article  Google Scholar 

  57. Krishnamoorthy N, Oriss T, Pagila M, Ray A, Ray P. A critical role for IL-6 secretion by dendritic cells promoting Th2 and limiting Th1 response. J Immunol. 2007;178:S181.

  58. Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013;73(3):1128–4.

    CAS  PubMed  Article  Google Scholar 

  59. Bode JG, Nimmesgern A, Schmitz J, Schaper F, Schmitt M, Frisch W, et al. LPS and TNFalpha induce SOCS3 mRNA and inhibit IL-6-induced activation of STAT3 in macrophages. FEBS Lett. 1999;463:365–70.

    CAS  PubMed  Article  Google Scholar 

  60. Nagasaki T, Hara M, Nakanishi H, Takahashi H, Sato M, Takeyama H. Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour–stroma interaction. Br J Cancer. 2014;110(2):469–78.

    CAS  PubMed  Article  Google Scholar 

  61. Nolen BM, Marks JR, Ta’san S, Rand A, Luong TM, Wang Y, et al. Serum biomarker profiles and response to neoadjuvant chemotherapy for locally advanced breast cancer. Breast Cancer Res. 2008;10(3):R45.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. Oh K, Lee OY, Shon SY, Nam O, Ryu PM, Seo MW, et al. A mutual activation loop between breast cancer cells and myeloid-derived suppressor cells facilitates spontaneous metastasis through IL-6 trans-signaling in a murine model. Breast Cancer Res. 2013;15(5):R79.

    PubMed  PubMed Central  Article  Google Scholar 

  63. Fisher DT, Appenheimer MM, Evans SS. The two faces of IL-6 in the tumor microenvironment. Semin Immunol. 2014;26(1):38–47.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Lederle W, Depner S, Schnur S, Obermueller E, Catone N, Just A, et al. IL-6 promotes malignant growth of skin SCCs by regulating a network of autocrine and paracrine cytokines. Int J Cancer. 2011;128(12):2803–14.

    CAS  PubMed  Article  Google Scholar 

  65. Gruys E, Toussaint MJM, Niewold TA, Koopmans SJ. Acute phase reaction and acute phase proteins. J Zhejiang Univ Sci B. 2005;6(11):1045–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW. Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood. 1994;83(1):113–8.

    CAS  PubMed  Google Scholar 

  67. Aderka D, Le JM, Vilcek J. IL-6 inhibits lipopolysaccharide induced tumor necrosis factor production in cultured human monocytes, U937 cells and in mice. J Immunol. 1989;143:3517–23.

    CAS  PubMed  Google Scholar 

  68. Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest. 1998;101(2):311–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Croker BA, Krebs DL, Zhang JG, Wormald S, Willson TA, Stanley EG, et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol. 2003;4:540–5.

    CAS  PubMed  Article  Google Scholar 

  70. Radtke S, Wüller S, Yang XP, Lippok BE, Mütze B, Mais C, et al. Cross-regulation of cytokine signalling: pro-inflammatory cytokines restrict IL-6 signalling through receptor internalisation and degradation. J Cell Sci. 2010;123(6):947–59.

    CAS  PubMed  Article  Google Scholar 

  71. Ahmed ST, Mayer A, Ji JD, Ivashkiv LB. Inhibition of IL-6 signaling by a p38-dependent pathway occurs in the absence of new protein synthesis. J Leukoc Biol. 2002;72:154–62.

    CAS  PubMed  Google Scholar 

  72. McLoughlin RM, Jenkins BJ, Grail D, Williams AS, Fielding CA, Parker CR, et al. IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation. Proc Natl Acad Sci U S A. 2005;102(27):9589–94.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. Curnow SJ, Scheel-Toellner D, Jenkinson W, Raza K, Durrani OM, Faint JM, et al. Inhibition of T cell apoptosis in the aqueous humor of patients with uveitis by IL-6/soluble IL-6 receptor trans-signaling. J Immunol. 2004;173(8):5290–7.

    CAS  PubMed  Article  Google Scholar 

  74. Atreya R, Mudter J, Finotto S, Müllberg J, Jostock T, Wirtz S, et al. Blockade of IL-6 transsignaling abrogates established experimental colitis in mice by suppression of the antiapoptotic resistance of lamina propria T cells. Nat Med. 2000;6(5):583–8.

    CAS  PubMed  Article  Google Scholar 

  75. Grivennikov S, Karin E, Terzic J, Mucida D, Yu G-Y, Vallabhapurapu S, et al. IL-6 and STAT3 signaling is required for survival of intestinal epithelial cells and colitis associated cancer. Cancer Cell. 2009;16:103–13.

    Article  CAS  Google Scholar 

  76. Barkhausen T, Tschernig T, Rosenstiel P, van Griensven M, Vonberg RP, Dorsch M, et al. Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model. Crit Care Med. 2011;39(6):1407–13.

    CAS  PubMed  Article  Google Scholar 

  77. Grivennikov SI, Karin M. Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann Rheum Dis. 2011;70 Suppl 1:i104–8.

    CAS  PubMed  Article  Google Scholar 

  78. Cozen W, Gill PS, Ingles SA, Masood R, Martinez-Maza O, Cockburn MG, et al. IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma. Blood. 2004;103:3216–21.

    CAS  PubMed  Article  Google Scholar 

  79. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317(5834):121–4.

    CAS  PubMed  Article  Google Scholar 

  80. Wei Q, Guo P, Mu K, Zhang Y, Zhao W, Huai W, et al. Estrogen suppresses hepatocellular carcinoma cells through ERβ-mediated upregulation of the NLRP3 inflammasome. Lab Investig. 2015;95(7):804–16.

    CAS  PubMed  Article  Google Scholar 

  81. Lin MT, Juan CY, Chang KJ, Chen WJ, Kuo ML. IL-6 inhibits apoptosis and retains oxidative DNA lesions in human gastric cancer AGS cells through up-regulation of anti-apoptotic gene mcl-1. Carcinogenesis. 2001;22(12):1947–53.

    CAS  PubMed  Article  Google Scholar 

  82. Jourdan M, Veyrune JL, Vos JD, Redal N, Couderc G, Klein B. A major role for Mcl-1 antiapoptotic protein in the IL-6-induced survival of human myeloma cells. Oncogene. 2003;22(19):2950–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. Wegiel B, Bjartell A, Culig Z, Persson JL. Interleukin-6 activates PI3K/Akt pathway and regulates cyclin A1 to promote prostate cancer cell survival. Int J Cancer. 2008;122(7):1521–9.

    CAS  PubMed  Article  Google Scholar 

  84. Zou M, Zhang X, Xu C. IL6-induced metastasis modulators p-STAT3, MMP-2 and MMP-9 are targets of 3,3′-diindolylmethane in ovarian cancer cells. Cell Oncol (Dordr). 2015;39:47–57.

    Article  CAS  Google Scholar 

  85. Mauer J, Denson JL, Brüning JC. Versatile functions for IL-6 in metabolism and cancer. Trends Immunol. 2015;36(2):92–101.

    CAS  PubMed  Article  Google Scholar 

  86. White JP, Puppa MJ, Gao S, Sato S, Welle SL, Carson JA. Muscle mTORC1 suppression by IL-6 during cancer cachexia: a role for AMPK. Am J Physiol Endocrinol Metab. 2013;304(10):E1042–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    CAS  PubMed  Article  Google Scholar 

  88. Herman JG. Hypermethylation of tumor suppressor genes in cancer. Semin Cancer Biol. 1999;9:359–67.

    CAS  PubMed  Article  Google Scholar 

  89. Hodge DR, Peng B, Cherry JC, Hurt EM, Fox SD, Kelley JA, et al. Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation. Cancer Res. 2005;65(11):4673–82.

    CAS  PubMed  Article  Google Scholar 

  90. Liu CC, Lin JH, Hsu TW, Su K, Li AF, Hsu HS, et al. IL-6 enriched lung cancer stem-like cell population by inhibition of cell cycle regulators via DNMT1 upregulation. Int J Cancer. 2015;136(3):547–59.

    CAS  PubMed  Google Scholar 

  91. Hodge DR, Cho E, Copeland TD, Guszczynski T, Yang E, Seth AK, et al. IL-6 enhances the nuclear translocation of DNA cytosine-5-methyltransferase 1 (DNMT1) via phosphorylation of the nuclear localization sequence by the AKT kinase. Cancer Genomics Proteomics. 2007;4(6):387–98.

    CAS  PubMed  Google Scholar 

  92. Gasche JA, Hoffmann J, Boland CR, Goel A. Interleukin-6 promotes tumorigenesis by altering DNA methylation in oral cancer cells. Int J Cancer. 2011;129(5):1053–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Nevins JR. The Rb/E2F pathway and cancer. Hum Mol Genet. 2001;10(7):699–703.

    CAS  PubMed  Article  Google Scholar 

  94. Giacinti C, Giordano A. RB and cell cycle progression. Oncogene. 2006;25(38):5220–7.

    CAS  PubMed  Article  Google Scholar 

  95. Urashima M, Ogata A, Chauhan D, Vidriales MB, Teoh G, Hoshi Y, et al. Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein. Blood. 1996;88(6):2219–27.

    CAS  PubMed  Google Scholar 

  96. Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, Thompson JF, et al. Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma. Mod Pathol. 2007;20(4):416–26.

    CAS  PubMed  Article  Google Scholar 

  97. Borhani N, Manoochehri M, Saleh-Gargari S, Ghaffari Novin M, Mansouri A, Omrani MD. Decreased expression of proapoptotic genes caspase-8- and BCL2-associated agonist of cell death (BAD) in ovarian cancer. Clin Ovarian Other Gynecol Cancer. 2014;7:8–23.

    Article  Google Scholar 

  98. Isomoto H, Kobayashi S, Werneburg NW, Bronk SF, Guicciardi ME, Frank DA, et al. Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells. Hepatology. 2005;42:1329–38.

    CAS  PubMed  Article  Google Scholar 

  99. Wei LH, Kuo ML, Chen CA, Chou CH, Cheng WF, Chang MC, et al. The anti-apoptotic role of interleukin-6 in human cervical cancer is mediated by up-regulation of Mcl-1 through a PI 3-K/Akt pathway. Oncogene. 2001;20(41):5799–809.

    CAS  PubMed  Article  Google Scholar 

  100. Jee SH, Chiu HC, Tsai TF, Tsai WL, Liao YH, Chu CY, et al. The phosphotidyl inositol 3-kinase/Akt signal pathway is involved in interleukin-6-mediated Mcl-1 upregulation and anti-apoptosis activity in basal cell carcinoma cells. J Investig Dermatol. 2002;119(5):1121–7.

    CAS  PubMed  Article  Google Scholar 

  101. Leu CM, Wong FH, Chang C, Huang SF, Hu CP. Interleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways. Oncogene. 2003;22(49):7809–18.

    CAS  PubMed  Article  Google Scholar 

  102. Garcia-Tuñón I, Ricote M, Ruiz A, Fraile B, Paniagua R, Royuela M. IL-6, its receptors and its relationship with bcl-2 and bax proteins in infiltrating and in situ human breast carcinoma. Histopathology. 2005;47(1):82–9.

    PubMed  Article  Google Scholar 

  103. Waxman AB, Kolliputi N. IL-6 protects against hyperoxia-induced mitochondrial damage via Bcl-2-induced Bak interactions with mitofusions. Am J Respir Cell Mol Biol. 2009;41(4):385–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. Brooks C, Wei Q, Feng L, Dong G, Tao Y, Mei L, et al. Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins. Proc Natl Acad Sci U S A. 2007;104:11649–54.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, et al. Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res. 2006;12(1):11–9.

    CAS  PubMed  Article  Google Scholar 

  106. Johnson C, Han YY, Nathan H, McCarra J, Alpini G, Meng F. Interleukin-6 and its receptor, key players in hepatobiliary inflammation and cancer. Transl Gastrointest Cancer. 2012;1:58–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Chen M-F, Lin P-Y, Wu C-F, Chen W-C, Wu C-T. IL-6 expression regulates tumorigenicity and correlates with prognosis in bladder cancer. PLoS ONE. 2013;8(4):e61901.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Hsu JH, Shi Y, Frost P, Yan H, Hoang B, Sharma S, et al. Interleukin-6 activates phosphoinositol-3′ kinase in multiple myeloma tumor cells by signaling through RAS-dependent, and separately, through p85-dependent pathways. Oncogene. 2004;23(19):3368–75.

    CAS  PubMed  Article  Google Scholar 

  109. Hideshima T, Nakamura N, Chauhan D, Anderson KC. Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene. 2001;20(42):5991–6000.

    CAS  PubMed  Article  Google Scholar 

  110. Borsellino N, Belldegrun A, Bonavida B. Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines. Cancer Res. 1995;55:4633–9.

    CAS  PubMed  Google Scholar 

  111. Suchi K, Fujiwara H, Okamura S, Okamura H, Umehara S, Todo M, et al. Overexpression of interleukin-6 suppresses cisplatin-induced cytotoxicity in esophageal squamous cell carcinoma cells. Anticancer Res. 2011;31(1):67–75.

    CAS  PubMed  Google Scholar 

  112. Hirano T, Ishihara K, Hibi M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene. 2000;19:2548–56.

    CAS  PubMed  Article  Google Scholar 

  113. Niu G, Wright KL, Ma Y, Wright GM, Huang M, Irby R, et al. Role of Stat3 in regulating p53 expression and function. Mol Cell Biol. 2005;25(17):7432–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. Patchen ML, MacVittie TJ, Williams JL, Schwartz GN, Souza LM. Administration of interleukin-6 stimulates multilineage hematopoiesis and accelerates recovery from radiation-induced hematopoietic depression. Blood. 1991;77(3):472–80.

    CAS  PubMed  Google Scholar 

  115. Kim SY, Kang JW, Song X, Kim BK, Yoo YD, Kwon YT, et al. Role of the IL-6–JAK1–STAT3–Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells. Cell Signal. 2013;25(4):961–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. Gupta PB, Fillmore CM, Jiang G, Shapira SD, Tao K, Kuperwasser C, et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011;146(4):633–44.

    CAS  PubMed  Article  Google Scholar 

  117. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30(7):1073–81.

    CAS  PubMed  Article  Google Scholar 

  119. Schiechl G, Bauer B, Fuss I, Lang SA, Moser C, Ruemmele P, et al. Tumor development in murine ulcerative colitis depends on MyD88 signaling of colonic F4/80+CD11bhighGr1low macrophages. J Clin Invest. 2011;121(5):1692–708.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441(7092):431–6.

    CAS  PubMed  Article  Google Scholar 

  121. Kesanakurti D, Chetty C, Maddirela DR, Gujrati M, Rao JS. Essential role of cooperative NF-kB and Stat3 recruitment to ICAM-1 intronic consensus elements in the regulation of radiation-induced invasion and migration in glioma. Oncogene. 2013;32(43):10.

    Article  CAS  Google Scholar 

  122. Warburg O. On the origin of cancer cells. Science. 1956;123:309–14.

    CAS  PubMed  Article  Google Scholar 

  123. Bhatt AN, Chauhan A, Khanna S, Rai Y, Singh S, Soni R, et al. Transient elevation of glycolysis confers radio-resistance by facilitating DNA repair in cells. BMC Cancer. 2015;15:335.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  124. 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(2):97–105.

    CAS  PubMed  Article  Google Scholar 

  125. Kawauchi K, Araki K, Tobiume K, Tanaka N. p53 regulates glucose metabolism through an IKK–NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol. 2008;10:611–8.

    CAS  PubMed  Article  Google Scholar 

  126. Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, et al. IL-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP activated protein kinase. Diabetes. 2006;55:2688–97.

    CAS  PubMed  Article  Google Scholar 

  127. Ghosh S, Ashcraft K. An IL-6 link between obesity and cancer. Front Biosci. 2013;5:461–78.

    Article  Google Scholar 

  128. Sarkar PD, Gopinath A, Skaria LK. Association of serum interleukin-6 and glycolysis in sickle cell disease patients. Med J DPU. 2014;7(3):317–20.

    Google Scholar 

  129. Valencia T, Kim JY, Abu-Baker S, Moscat-Pardos J, Ahn CS, Reina-Campos M, et al. Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis. Cancer Cell. 2014;26(1):121–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. Mercurio F, Manning AM. NF-kappaB as a primary regulator of the stress response. Oncogene. 1999;18(45):6163–71.

    CAS  PubMed  Article  Google Scholar 

  131. Kratsovnik E, Bromberg Y, Sperling O, Zoref-Shani E. Oxidative stress activates transcription factor NF-kB-mediated protective signaling in primary rat neuronal cultures. J Mol Neurosci. 2005;26(1):27–32.

    CAS  PubMed  Article  Google Scholar 

  132. Libermann TA, Baltimore D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol. 1990;10(5):2327–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. Wang L, Walia B, Evans J, Gewirtz AT, Merlin D, Sitaraman SV. IL-6 induces NF-kappa B activation in the intestinal epithelia. J Immunol. 2003;171(6):3194–201.

    CAS  PubMed  Article  Google Scholar 

  134. Grivennikov S, Karin M. Dangerous liaisons: STAT3 and NF-kB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 2010;21(1):11–9.

    CAS  PubMed  Article  Google Scholar 

  135. Brown CO, Salem K, Wagner BA, Bera S, Singh N, Tiwari A, et al. Interleukin-6 counteracts therapy-induced cellular oxidative stress in multiple myeloma by up-regulating manganese superoxide dismutase. Biochem J. 2012;444(3):515–27.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49(11):1603–16.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. Jia Y, Zhou F, Deng P, Fan Q, Li C, Liu Y, et al. Interleukin 6 protects H(2)O(2)-induced cardiomyocytes injury through upregulation of prohibitin via STAT3 phosphorylation. Cell Biochem Funct. 2012;30(5):426–31.

    CAS  PubMed  Article  Google Scholar 

  138. Craig R, Larkin A, Mingo AM, Thuerauf DJ, Andrews C, McDonough PM, et al. p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system. J Biol Chem. 2000;275(31):23814–24.

    CAS  PubMed  Article  Google Scholar 

  139. Kalluri R, Weinberg RA. The basics of epithelial–mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. Ricciardi M, Zanotto M, Malpeli G, Bassi G, Perbellini O, Chilosi M, et al. Epithelial-to-mesenchymal transition (EMT) induced by inflammatory priming elicits mesenchymal stromal cell-like immune-modulatory properties in cancer cells. Br J Cancer. 2015;112(6):1067–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. Tawara K, Oxford JT, Jorcyk CL. Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies. Cancer Manag Res. 2011;3:177–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Helbig G, Christopherson 2nd KW, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, et al. NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem. 2003;278(24):21631–8.

    CAS  PubMed  Article  Google Scholar 

  143. 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(12):3988–4002.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86(3):353–64.

    CAS  PubMed  Article  Google Scholar 

  145. Kujawski M, Kortylewski M, Lee H, Herrmann A, Kay H, Yu H. Stat3 mediates myeloid cell dependent tumor angiogenesis in mice. J Clin Invest. 2008;118(10):3367–77.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. Houde C, Li Y, Song L, Barton K, Zhang Q, Godwin J, et al. Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines. Blood. 2004;104(12):3697–704.

    CAS  PubMed  Article  Google Scholar 

  147. Yun UJ, Park SE, Jo YS, Kim J, Shin DY. DNA damage induces the IL-6/STAT3 signaling pathway, which has anti-senescence and growth-promoting functions in human tumors. Cancer Lett. 2012;323(2):155–60.

    CAS  PubMed  Article  Google Scholar 

  148. Rodier F, Coppé JP, Patil CK, Hoeijmakers WA, Muñoz DP, Raza SR, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009;11:973–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. Gilbert LA, Hemann MT. DNA damage-mediated induction of a chemoresistant niche. Cell. 2010;143:355–66.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. Wu ZH, Wong ET, Shi Y, Niu J, Chen Z, Miyamoto S, et al. ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-mediated IKK activation in response to genotoxic stress. Mol Cell. 2010;40:75–86.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. Tachibana S, Zhang X, Ito K, Ota Y, Cameron AM, Williams GM, et al. Interleukin-6 is required for cell cycle arrest and activation of DNA repair enzymes after partial hepatectomy in mice. Cell Biosci. 2014;4(1):6.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  152. Chang L, Guo R, Huang Q, Yen Y. Chromosomal instability triggered by Rrm2b loss leads to IL-6 secretion and plasmacytic neoplasms. Cell Rep. 2013;3(5):1389–97.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. Deorukhkar A, Krishnan S. Targeting inflammatory pathways for tumor radiosensitization. Biochem Pharmacol. 2010;80(12):1904–14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–99.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. Woods Ignatoski KM, Friedman J, Escara-Wilke J, Zhang X, Daignault S, Dunn RL, et al. Change in markers of bone metabolism with chemotherapy for advanced prostate cancer: interleukin-6 response is a potential early indicator of response to therapy. J Interferon Cytokine Res. 2008;29(2):105–12.

    Article  CAS  Google Scholar 

  156. Conze D, Weiss L, Regen PS, Bhushan A, Weaver D, Johnson P, et al. Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. Cancer Res. 2001;61:8851–8.

    CAS  PubMed  Google Scholar 

  157. Patel SAA, Bhambra U, Charalambous MP, David RM, Edwards RJ, Lightfoot T, et al. Interleukin-6 mediated upregulation of CYP1B1 and CYP2E1 in colorectal cancer involves DNA methylation, miR27b and STAT3. Br J Cancer. 2014;111(12):2287–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. Bochet L, Meulle A, Imbert S, Salles B, Valet P, Muller C. Cancer-associated adipocytes promotes breast tumor radioresistance. Biochem Biophys Res Commun. 2011;1:102–6.

    Article  CAS  Google Scholar 

  159. Xu H, Lai W, Zhang Y, Liu L, Luo X, Zeng Y, et al. Tumor-associated macrophage-derived IL-6 and IL-8 enhance invasive activity of LoVo cells induced by PRL-3 in a KCNN4 channel-dependent manner. BMC Cancer. 2014;14:330.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  160. Touboul C, Lis R, Al Farsi H, Raynoud CM, Warfa M, Althawadi H, et al. Mesenchymal stem cells enhances ovarian cancer cell infiltration through IL-6 secretion in an amniochorionic membrane based 3D model. J Transl Med. 2013;11:28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. Eicthen A, Su J, Adler A, Zhang L, Loffe E, Parveen AA, et al. Resistance to anti-VEGF therapy mediated by autocrine IL-6/STAT3 signaling and overcome by IL-6 blockade. Cancer Res. 2016;76:2327–39.

  162. Korkaya H, Kim GI, Davis A, Malik F, Henry NL, Ithimakin S, et al. Activation of IL-6 inflammatory loop mediates transtuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell. 2012;47(4):570–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. Chen F, Zhuang X, Lin L, Yu P, Wang Y, Shi Y, et al. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med. 2015;13:45.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  164. Kontzias A, Kotlyar A, Laurence A, Changelian P, O’Shea JJ. Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr Opin Pharmacol. 2012;12(4):464–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. Karkera J, Steiner H, Li W, Skradski V, Moser PL, Riethdorf S, et al. The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study. Prostate. 2011;71(13):1455–65.

    CAS  PubMed  Article  Google Scholar 

  166. Chen R, Chen B. Siltuximab (CNTO 328): a promising option for human malignancies. Drug Des Devel Ther. 2015;9:3455–8.

    PubMed  PubMed Central  Article  Google Scholar 

  167. Chou CH, Wei LH, Kuo ML, Huang YJ, Lai KP, Chen CA, et al. Up-regulation of interleukin-6 in human ovarian cancer cell via a Gi/PI3K-Akt/NF-kappaB pathway by lysophosphatidic acid, an ovarian cancer-activating factor. Carcinogenesis. 2005;26(1):45–52.

    CAS  PubMed  Article  Google Scholar 

  168. Song L, Smith MA, Doshi P, Sasser K, Fulp W, Altiok S, et al. Antitumor efficacy of the anti-interleukin-6 (IL-6) antibody siltuximab in mouse xenograft models of lung cancer. J Thorac Oncol. 2014;9(7):974–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. Bagcchi S. Siltuximab in transplant-ineligible patients with myeloma. Lancet Oncol. 2014;15(8):e309.

    PubMed  Article  Google Scholar 

  170. Emilie D, Wijdenes J, Gisselbrecht C, Jarrousse B, Billaud E, Blay JY, et al. Administration of an anti-interleukin-6 monoclonal antibody to patients with acquired immunodeficiency syndrome and lymphoma: effect on lymphoma growth and on B clinical symptoms. Blood. 1994;84:2472–9.

    CAS  PubMed  Google Scholar 

  171. Asbagh LA, Uzunoglu S, Cal C. Zoledronic acid effects interleukin-6 expression in hormone findependent prostate cancer cell lines. Int Braz J Urol. 2008;34(3):355–64.

    PubMed  Article  Google Scholar 

  172. Gnant M. Zoledronic acid in breast cancer: latest findings and interpretations. Ther Adv Med Oncol. 2011;3(6):293–301.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. Kurebayashi J, Yamamoto S, Otsuki T, Sonoo H. Medroxyprogesterone acetate inhibits interleukin 6 secretion from KPL-4 human breast cancer cells both in vitro and in vivo: a possible mechanism of the anticachectic effect. Br J Cancer. 1999;79(3/4):631–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. Shinriki S, Jono H, Ota K, Ueda M, Kudo M, Ota T, et al. Humanized anti-interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma. Clin Cancer Res. 2009;15(17):5426–34.

    CAS  PubMed  Article  Google Scholar 

  175. Ando K, Takahashi F, Kato M, Kaneko N, Doi T, Ohe Y, et al. Tocilizumab, a proposed therapy for the cachexia of interleukin6-expressing lung cancer. PLoS One. 2014;9(7):e102436.

    PubMed  PubMed Central  Article  Google Scholar 

  176. Moreau P, Harousseau JL, Wijdenes J, Morineau N, Milpied N, Bataille R. A combination of anti-interleukin 6 murine monoclonal antibody with dexamethasone and high-dose melphalan induces high complete response rates in advanced multiple myeloma. Br J Haematol. 2000;109:661–4.

    CAS  PubMed  Article  Google Scholar 

  177. Tai YT, Anderson KC. Antibody-based therapies in multiple myeloma. Bone Marrow Res. 2011;2011:924058.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  178. Isobe A, Sawada K, Kinose Y, Ohyagi-Hara C, Nakatsuka E, Makino H, et al. Interleukin 6 receptor is an independent prognostic factor and a potential therapeutic target of ovarian cancer. PLoS ONE. 2015;10(2):e0118080.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  179. Jiang XP, Yang DC, Elliott RL, Head JF. Down-regulation of expression of interleukin-6 and its receptor results in growth inhibition of MCF-7 breast cancer cells. Anticancer Res. 2011;31:2899–906.

    CAS  PubMed  Google Scholar 

  180. Sun Y, Moretti L, Giacalone NJ, Schleicher S, Speirs CK, Carbone DP, et al. Inhibition of JAK2 signaling by TG101209 enhances radiotherapy in lung cancer models. J Thorac Oncol. 2011;6(4):699–706.

    PubMed  PubMed Central  Article  Google Scholar 

  181. Ramakrishnan V, Kimlinger T, Haug J, Timm M, Wellik L, Halling T, et al. TG101209, a novel JAK2 inhibitor, has significant in-vitro activity in multiple myeloma and displays preferential cytotoxicity for CD45+ myeloma cells. Am J Hematol. 2010;85(9):675–86.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. Kobayashi A, Tanizaki Y, Kimura A, Ishida Y, Nosaka M, Toujima S, et al. AG490, a Jak2 inhibitor, suppressed the progression of murine ovarian cancer. Eur J Pharmacol. 2015;766:63–75.

    CAS  PubMed  Article  Google Scholar 

  183. Eghtedar A, Verstovsek S, Estrov Z, Burger J, Cortes J, Bivins C, et al. Phase II study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including post myeloproliferative neoplasms (MPN) acute myeloid leukemia (AML). Blood. 2012;119(20):4614–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. Seavey MM, Lu LD, Stump KL, Wallace NH, Hockeimer W, O’Kane TM, et al. Therapeutic efficacy of CEP-33779, a novel selective JAK2 inhibitor, in a mouse model of colitis-induced colorectal cancer. Mol Cancer Ther. 2012;11(4):984–93.

    CAS  PubMed  Article  Google Scholar 

  185. Hart S, Goh KC, Novotny-Diermayr V, Tan YC, Madan B, Amalini C, et al. Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia. Blood Cancer J. 2011;1(11):e44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. Yang F, Brown C, Buettner R, Hedvat M, Starr R, Scuto A, et al. Sorafenib induces growth arrest and apoptosis of human glioblastoma cells through the dephosphorylation of signal transducers and activators of transcription 3. Mol Cancer Ther. 2010;9(4):953–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  187. Duan Z, Bradner JE, Greenberg E, Levine R, Foster R, Mahoney J, et al. SD-1029 inhibits signal transducer and activator of transcription 3 nuclear translocation. Clin Cancer Res. 2006;12(22):6844–52.

    CAS  PubMed  Article  Google Scholar 

  188. Shi X, Franko B, Frantz C, Amin HM, Lai R, et al. JSI-124 (cucurbitacin I) inhibits Janus kinase-3/signal transducer and activator of transcription-3 signalling, downregulates nucleophosmin-anaplastic lymphoma kinase (ALK), and induces apoptosis in ALK-positive anaplastic large cell lymphoma cells. Br J Haematol. 2006;135(1):26–32.

    CAS  PubMed  Article  Google Scholar 

  189. Su Y, Li G, Zhang X, Gu J, Zhang C, Tian Z, et al. JSI-124 inhibits glioblastoma multiforme cell proliferation through G2/M cell cycle arrest and apoptosis augment. Cancer Biol Ther. 2008;7(8):1243–9.

    CAS  PubMed  Article  Google Scholar 

  190. Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM. Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res. 2003;63(6):1270–9.

    CAS  PubMed  Google Scholar 

  191. Gholam P. The role of sorafenib in hepatocellular carcinoma. Clin Adv Hematol Oncol. 2015;13(4):232–4.

    PubMed  Google Scholar 

  192. Moreno-Aspitia A. Clinical overview of sorafenib in breast cancer. Future Oncol. 2010;6(5):655–63.

    CAS  PubMed  Article  Google Scholar 

  193. Jäger D, Ma JH, Mardiak J, Ye DW, Korbenfeld E, Zemanova M, et al. Sorafenib treatment of advanced renal cell carcinoma patients in daily practice: the large international PREDICT Study. Clin Genitourin Cancer. 2015;13(2):156–64.e1.

    PubMed  Article  Google Scholar 

  194. Moreira RB, Peixoto RD, de Sousa Cruz MR. Clinical response to sorafenib in a patient with metastatic colorectal cancer and FLT3 amplification. Case Rep Oncol. 2015;8(1):83–7.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  195. Tanaka T, Narazaki M, Kishimoto T. Anti-interleukin-6 receptor antibody, tocilizumab, for the treatment of autoimmune diseases. FEBS Lett. 2011;585(23):3699–709.

    CAS  PubMed  Article  Google Scholar 

  196. Trikha M, Corringham R, Klein B, Rossi J-F. Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res. 2003;9(13):4653–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Coward J, Kulbe H, Chakravarty P, Leader D, Vassileva V, Leinster DA, et al. Interleukin-6 as a therapeutic target in human ovarian cancer. Clin Cancer Res. 2011;17(18):6083–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  198. Guan M, Zhou YP, Sun JL, Chen SC. Adverse events of monoclonal antibodies used for cancer therapy. Biomed Res Int. 2015;2015:428169.

    PubMed  PubMed Central  Google Scholar 

  199. Chen MF, Hsieh CC, Chen WC, Lai CH. Role of interleukin-6 in the radiation response of liver tumors. Int J Radiat Oncol Biol Phys. 2012;84(5):e621–30.

    CAS  PubMed  Article  Google Scholar 

  200. Judd LM, Menheniott TR, Ling H, Jackson CB, Howlett M, Kalantzis A, et al. Inhibition of the JAK2/STAT3 pathway reduces gastric cancer growth in vitro and in vivo. PLoS One. 2014;9(5):e95993.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  201. Huang C, Yang G, Jiang T, Huang K, Cao J, Qiu Z. Effects of IL-6 and AG490 on regulation of Stat3 signaling pathway and invasion of human pancreatic cancer cells in vitro. J Exp Clin Cancer Res. 2010;29(1):51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. Xiong A, Yang Z, Shen Y, Zhou J, Shen Q. Transcription factor STAT3 as a novel molecular target for cancer prevention. Cancers. 2014;6(2):926–57.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  203. Ishdorj G, Johnston JB, Gibson SB. Inhibition of constitutive activation of STAT3 by curcurbitacin-I (JSI-124) sensitized human B-leukemia cells to apoptosis. Mol Cancer Ther. 2010;9(12):3302–14.

    CAS  PubMed  Article  Google Scholar 

  204. Schust J, Sperl B, Hollis A, Mayer TU, Berg T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol. 2006;13(11):1235–42.

    CAS  PubMed  Article  Google Scholar 

  205. Yu X, He L, Cao P, Yu Q. Eriocalyxin B inhibits STAT3 signaling by covalently targeting STAT3 and blocking phosphorylation and activation of STAT3. PLoS ONE. 2015;10(5):e0128406.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  206. Jing N, Li Y, Xiong W, Sha W, Jing L, Tweardy DJ. G-quartet oligonucleotides: a new class of signal transducer and activator of transcription 3 inhibitors that suppresses growth of prostate and breast tumors through induction of apoptosis. Cancer Res. 2004;64(18):6603–9.

    CAS  PubMed  Article  Google Scholar 

  207. Jing N, Zhu Q, Yuan P, Li Y, Mao L, Tweardy DJ. Targeting signal transducer and activator of transcription 3 with G-quartet oligonucleotides: a potential novel therapy for head and neck cancer. Mol Cancer Ther. 2006;5(2):279–86.

    CAS  PubMed  Article  Google Scholar 

  208. Yue P, Turkson J. Targeting STAT3 in cancer: how successful are we? Expert Opin Investig Drugs. 2009;18(1):45–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  209. Chen CL, Loy A, Cen L, Chan C, Hsieh FC, Cheng G, et al. Signal transducer and activator of transcription 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells. BMC Cancer. 2007;7:111.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  210. Song H, Wang R, Wang S, Lin J. A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. Proc Natl Acad Sci U S A. 2005;102(13):4700–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  211. Weidler M, Rether J, Anke T, Erkel G. Inhibition of interleukin-6 signaling by galiellalactone. FEBS Lett. 2000;484(1):1–6.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgments

NK thanks the Defence Research and Development Organization, Government of India, for fellowship support. We acknowledge Director INMAS for constant support and encouragement.

Author information

Authors and Affiliations

  1. Division of Metabolic Cell Signalling Research, Institute of Nuclear Medicine and Allied Sciences, Brig SK Mazumdar Road, Delhi, 110 054, India

    Neeraj Kumari & Anant Narayan Bhatt

  2. Department of Biotechnology, Delhi Technological University, Delhi, 110042, India

    Neeraj Kumari & Asmita Das

  3. Central Research Facility, Sri Ramachandra University, Chennai, 600116, India

    B. S. Dwarakanath

Authors
  1. Neeraj Kumari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. S. Dwarakanath
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Asmita Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anant Narayan Bhatt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anant Narayan Bhatt.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kumari, N., Dwarakanath, B.S., Das, A. et al. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumor Biol. 37, 11553–11572 (2016). https://doi.org/10.1007/s13277-016-5098-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5098-7

Keywords

  • IL-6
  • Cancer
  • Therapeutic resistance
  • STAT-3
  • Chemotherapy
  • Radio-resistance