Role of interleukin-6 in cancer progression and therapeutic resistance (original) (raw)

• Bromberg J, Wang TC. Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell. 2009;15:79–80.
  Article CAS PubMed PubMed Central Google Scholar
• Grivennikov S, Karin M. Autocrine IL-6 signaling: a key event in tumorigenesis? Cancer Cell. 2008;13:7–9.
  Article CAS PubMed Google Scholar
• Waldner MJ, Foersch S, Neurath MF. Interleukin-6—a key regulator of colorectal cancer development. Int J Biol Sci. 2012;8(9):1248–53.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• Culig Z, Puhr M. Interleukin-6: a multifunctional targetable cytokine in human prostate cancer. Mol Cell Endocrinol. 2012;360(1–2):52–8.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article PubMed CAS Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• Altundag O, Altundag K, Gunduz E. Interleukin-6 and C-reactive protein in metastatic renal cell carcinoma. J Clin Oncol. 2005;23:1044.
  Article PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article PubMed PubMed Central CAS Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• Veuger SJ, Hunter JE, Durkacz BW. Ionizing radiation-induced NF-kappaB activation requires PARP-1 function to confer radioresistance. Oncogene. 2009;28:832–42.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• Naugler WE, Karin M. NF-kappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev. 2008;18(1):19–26.
  Article CAS PubMed PubMed Central Google Scholar
• Wolf J, Rose-John S, Garbers C. Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine. 2014;70(1):11–20.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin-6 family of cytokines and gp130. Blood. 1995;86:1243–54.
  CAS PubMed Google Scholar
• 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.
  Article CAS Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• Taga T, Kishimoto T. Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol. 1997;15:797–819.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• Akira S, Kishimoto T. IL-6 and NF-IL6 in acute-phase response and viral infection. Immunol Rev. 1992;127:25–50.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• Zhao W, Liu M, Kirkwood KL. p38alpha stabilizes interleukin-6 mRNA via multiple AU-rich elements. J Biol Chem. 2008;283(4):1778–85.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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
• 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
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS Google Scholar
• Angstwurm MW, Gartner R, Ziegler-Heitbrock HW. Cyclic plasma IL-6 levels during normal menstrual cycle. Cytokine. 1997;9:370–4.
  Article CAS PubMed Google Scholar
• Reihmane D, Dela F. Interleukin-6: possible biological roles during exercise. Eur J Sport Sci. 2014;14(3):242–50.
  Article PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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
• 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.
  Article PubMed Google Scholar
• 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
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article PubMed PubMed Central CAS Google Scholar
• 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.
  Article PubMed PubMed Central Google Scholar
• Fisher DT, Appenheimer MM, Evans SS. The two faces of IL-6 in the tumor microenvironment. Semin Immunol. 2014;26(1):38–47.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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
• 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
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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
• Mauer J, Denson JL, Brüning JC. Versatile functions for IL-6 in metabolism and cancer. Trends Immunol. 2015;36(2):92–101.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.
  Article CAS PubMed Google Scholar
• Herman JG. Hypermethylation of tumor suppressor genes in cancer. Semin Cancer Biol. 1999;9:359–67.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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
• 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
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• Nevins JR. The Rb/E2F pathway and cancer. Hum Mol Genet. 2001;10(7):699–703.
  Article CAS PubMed Google Scholar
• Giacinti C, Giordano A. RB and cell cycle progression. Oncogene. 2006;25(38):5220–7.
  Article CAS PubMed Google Scholar
• 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
• 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.
  Article CAS PubMed Google Scholar
• 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
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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
• 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
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article PubMed PubMed Central CAS Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441(7092):431–6.
  Article CAS PubMed Google Scholar
• 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
• Warburg O. On the origin of cancer cells. Science. 1956;123:309–14.
  Article CAS PubMed Google Scholar
• 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.
  Article PubMed PubMed Central CAS Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• Ghosh S, Ashcraft K. An IL-6 link between obesity and cancer. Front Biosci. 2013;5:461–78.
  Article Google Scholar
• 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
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• Mercurio F, Manning AM. NF-kappaB as a primary regulator of the stress response. Oncogene. 1999;18(45):6163–71.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• Grivennikov S, Karin M. Dangerous liaisons: STAT3 and NF-kB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 2010;21(1):11–9.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• Kalluri R, Weinberg RA. The basics of epithelial–mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86(3):353–64.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• Gilbert LA, Hemann MT. DNA damage-mediated induction of a chemoresistant niche. Cell. 2010;143:355–66.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article PubMed PubMed Central CAS Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• Deorukhkar A, Krishnan S. Targeting inflammatory pathways for tumor radiosensitization. Biochem Pharmacol. 2010;80(12):1904–14.
  Article CAS PubMed PubMed Central Google Scholar
• Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–99.
  Article CAS PubMed PubMed Central Google Scholar
• 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
• 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
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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
• 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.
  Article PubMed PubMed Central CAS Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article PubMed PubMed Central CAS Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• Chen R, Chen B. Siltuximab (CNTO 328): a promising option for human malignancies. Drug Des Devel Ther. 2015;9:3455–8.
  Article PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• Bagcchi S. Siltuximab in transplant-ineligible patients with myeloma. Lancet Oncol. 2014;15(8):e309.
  Article PubMed Google Scholar
• 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
• 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.
  Article PubMed Google Scholar
• Gnant M. Zoledronic acid in breast cancer: latest findings and interpretations. Ther Adv Med Oncol. 2011;3(6):293–301.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• Tai YT, Anderson KC. Antibody-based therapies in multiple myeloma. Bone Marrow Res. 2011;2011:924058.
  Article PubMed PubMed Central CAS Google Scholar
• 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.
  Article PubMed PubMed Central CAS Google Scholar
• 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
• 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.
  Article PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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
• Gholam P. The role of sorafenib in hepatocellular carcinoma. Clin Adv Hematol Oncol. 2015;13(4):232–4.
  PubMed Google Scholar
• Moreno-Aspitia A. Clinical overview of sorafenib in breast cancer. Future Oncol. 2010;6(5):655–63.
  Article CAS PubMed Google Scholar
• 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.
  Article PubMed Google Scholar
• 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.
  Article PubMed PubMed Central CAS Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article PubMed PubMed Central CAS Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article PubMed PubMed Central CAS Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article PubMed PubMed Central CAS Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• Yue P, Turkson J. Targeting STAT3 in cancer: how successful are we? Expert Opin Investig Drugs. 2009;18(1):45–56.
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article PubMed PubMed Central CAS Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• Weidler M, Rether J, Anke T, Erkel G. Inhibition of interleukin-6 signaling by galiellalactone. FEBS Lett. 2000;484(1):1–6.
  Article CAS PubMed Google Scholar