Nuclear Factors Linking Cancer and Inflammation

  • Kunzang Chosdol
  • Mohita Bhagat
  • Bhawana Dikshit
  • Evanka Madan
  • Parthaprasad Chattopadhyay
  • Subrata Sinha
Part of the Cancer Drug Discovery and Development book series (CDD&D)


An association between inflammation and cancer has long-been known, but the past decade has witnessed a spurt in the research linking the two processes. On the one hand chronic inflammation predisposes to cancer, on the other, neoplastic transformation predisposes towards an intrinsic pro-inflammatory microenvironment, which further promotes the progression of the malignancy. Irrespective of the stimulus, whether extrinsic (bacteria, viruses, non-healing wounds, irritants etc.) or intrinsic (oncogenes, protein kinases etc.), all signals that trigger the inflammatory microenvironment in tumor cells converge in the nucleus and coordinate inflammatory transcriptional activity by activating various nuclear/transcription factors. This forms a vicious cycle, further promoting inflammation, facilitating tumor progression, proliferation, survival and angiogenesis. This chapter focuses on transcriptional mediators intrinsic to tumour cells that enhance the inflammatory processes.

The well known nuclear/transcription factors important for this linkage are NFkB, HIF1α, AP-1 and STAT-3. The cross talk between these factors results in a complex web of signalling processes that have a marked influence on the cellular phenotype, cell-cell interactions and the interaction of the tumour with the microenvironment. This chapter focuses on the above mentioned factors and their effects, while also looking at the possibilities of utilising the same for therapeutic intervention.


Transcription factors NFkB AP-1 STAT3 HIF1α Cancer Inflammation 





Activator protein 1

ARP 2/3

Actin-related protein 2/3 complex subunit 1B


Activating transcription factor




BCL2-associated X protein


B-cell CLL/lymphoma 2


B-cell lymphoma-extra large


Capping protein (actin filament)


Baculoviral IAP repeat-containing protein 3


Proto-oncogene c-Rel




cAMP response element


Chemokine (C-X-C motif) ligand




Dextran-sulphate sodium


Epidermal growth factor


Epidermal growth factor


Epithelial-Mesenchymal Transition


Extracellular signal-regulated kinase


Factor inhibiting HIF


FBJ murine osteosarcoma viral oncogene homolog


Fos–gene family member


Glioblastoma multifome


Granulocyte-macrophage colony-stimulating factor


Hypoxia-inducible factor 1 α




Immunoglobulin (Ig)-like intercellular adhesion molecule


Inhibitor of kappa light polypeptide gene enhancer in B-cells


IκB kinase


Interleukin 1-beta


Inducible Nitric acid synthase


c-Jun N-terminal kinase


jun proto-oncogene


Keratinocyte chemokine


Bacterial lipopolysaccharides


Musculoaponeurotic fibrosarcoma


Mitogen-activated protein kinase


Myeloid cell leukemia sequence 1


Major intrinsic protein of lens fiber


Matrix metalloproteinase


Mucin 1, cell surface associated


v-myc myelocytomatosis viral oncogene homolog


NF-kappa B essential modulator also known as IKKγ


Nuclear factor kappa-light-chain-enhancer of activated B cells


NF-κB inducing kinase


Nonsteroidal anti-inflammatory drug


Programmed cell death protein 4


Proline hydroxylases


Proto-oncogene serine/threonine-protein kinase


Phosphatase and tensin homolog


v-raf-1 murine leukemia viral oncogene homolog


RAS oncogene


v-rel reticuloendotheliosis viral oncogene homolog A


v-rel reticuloendotheliosis viral oncogene homolog B


Rel homology domain


Reactive nitrogen species


Reactive oxygen species


Secreted protein acidic and rich in cysteines


Signal transducer and activator of transcription 3


Signal transducer and activator of transcription 6


Tumor associated macrophages


Transforming growth factor beta


Tumor necrosis factor


12-0-tetradecanoylphorbol 13-acetate


Transgenic adenocarcinoma of mouse prostrate


TPA response element


Twist homolog (Drosophila)


Vascular endothelial growth factor


Von Hipple Lindau


Zinc finger E-box binding homeobox



Research work of the authors cited in the text is funded by Defence Research and Development Organization (DRDO), India and Department of Biotechnology (DBT), India. Authors are grateful to National Brain Research Centre (NBRC), Manesar, Gurgaon, India for the facilities and co-support.


  1. 1.
    Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G (2006) Inflammation and cancer: how hot is the link? Biochem Pharmacol 72(11):1605–1621PubMedCrossRefGoogle Scholar
  2. 2.
    Kuper H, Adami HO, Trichopoulos D (2000) Infections as a major preventable cause of human cancer. J Intern Med 248(3):171–183PubMedCrossRefGoogle Scholar
  3. 3.
    Wang R, Zhou SLi S (2011) Cancer therapeutic agents targeting hypoxia-inducible factor-1. Curr Med Chem 18(21):3168–3189PubMedCrossRefGoogle Scholar
  4. 4.
    Shabad LM (1962) Some experimental data regarding the relationship between inflammation and cancer. Vopr Onkol 8(6):74–80PubMedGoogle Scholar
  5. 5.
    Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899PubMedCrossRefGoogle Scholar
  6. 6.
    Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867PubMedCrossRefGoogle Scholar
  7. 7.
    Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545PubMedCrossRefGoogle Scholar
  8. 8.
    de Martel C, Ferlay J, Franceschi S, Vignat J, Bray F, Forman D et al (2012) Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol 13(6):607–615PubMedCrossRefGoogle Scholar
  9. 9.
    Kopp E, Ghosh S (1994) Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 265(5174):956–959PubMedCrossRefGoogle Scholar
  10. 10.
    Aggarwal BB, Gehlot P (2009) Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol 9(4):351–369PubMedCrossRefGoogle Scholar
  11. 11.
    Borrello MG, Degl’Innocenti D, Pierotti MA (2008) Inflammation and cancer: the oncogene-driven connection. Cancer Lett 267(2):262–270PubMedCrossRefGoogle Scholar
  12. 12.
    Schwartsburd PM (2004) Age-promoted creation of a pro-cancer microenvironment by inflammation: pathogenesis of dyscoordinated feedback control. Mech Ageing Dev 125(9):581–590PubMedCrossRefGoogle Scholar
  13. 13.
    Borrello MG, Alberti L, Fischer A, Degl’innocenti D, Ferrario C, Gariboldi M et al (2005) Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. Proc Natl Acad Sci USA 102(41):14825–14830PubMedCrossRefGoogle Scholar
  14. 14.
    De Falco V, Guarino V, Avilla E, Castellone MD, Salerno P, Salvatore G et al (2007) Biological role and potential therapeutic targeting of the chemokine receptor CXCR4 in undifferentiated thyroid cancer. Cancer Res 67(24):11821–11829PubMedCrossRefGoogle Scholar
  15. 15.
    Xu K, Shu HK (2007) EGFR activation results in enhanced cyclooxygenase-2 expression through p38 mitogen-activated protein kinase-dependent activation of the Sp1/Sp3 transcription factors in human gliomas. Cancer Res 67(13):6121–6129PubMedCrossRefGoogle Scholar
  16. 16.
    Guerra C, Schuhmacher AJ, Canamero M, Grippo PJ, Verdaguer L, Perez-Gallego L et al (2007) Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11(3):291–302PubMedCrossRefGoogle Scholar
  17. 17.
    Sparmann A, Bar-Sagi D (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6(5):447–458PubMedCrossRefGoogle Scholar
  18. 18.
    Sumimoto H, Imabayashi F, Iwata T, Kawakami Y (2006) The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med 203(7):1651–1656PubMedCrossRefGoogle Scholar
  19. 19.
    Shchors K, Shchors E, Rostker F, Lawlor ER, Brown-Swigart L, Evan GI (2006) The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1beta. Genes Dev 20(18):2527–2538PubMedCrossRefGoogle Scholar
  20. 20.
    Schonthaler HB, Guinea-Viniegra J, Wagner EF (2011) Targeting inflammation by modulating the Jun/AP-1 pathway. Ann Rheum Dis 70(Suppl 1):i109–i112PubMedCrossRefGoogle Scholar
  21. 21.
    Bonizzi G, Karin M (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25(6):280–288PubMedCrossRefGoogle Scholar
  22. 22.
    Perkins ND (2012) The diverse and complex roles of NF-kappaB subunits in cancer. Nat Rev Cancer 12(2):121–132PubMedGoogle Scholar
  23. 23.
    Koul D, Shen R, Shishodia S, Takada Y, Bhat KP, Reddy SA et al (2007) PTEN down regulates AP-1 and targets c-fos in human glioma cells via PI3-kinase/Akt pathway. Mol Cell Biochem 300(1–2):77–87PubMedCrossRefGoogle Scholar
  24. 24.
    Qin H, Wilson CA, Lee SJ, Zhao X, Benveniste EN (2005) LPS induces CD40 gene expression through the activation of NF-kappaB and STAT-1alpha in macrophages and microglia. Blood 106(9):3114–3122PubMedCrossRefGoogle Scholar
  25. 25.
    Fitzgerald DC, Meade KG, McEvoy AN, Lillis L, Murphy EP, MacHugh DE et al (2007) Tumour necrosis factor-alpha (TNF-alpha) increases nuclear factor kappaB (NFkappaB) activity in and interleukin-8 (IL-8) release from bovine mammary epithelial cells. Vet Immunol Immunopathol 116(1–2):59–68PubMedCrossRefGoogle Scholar
  26. 26.
    Fan Y, Dutta J, Gupta N, Fan G, Gelinas C (2008) Regulation of programmed cell death by NF-kappaB and its role in tumorigenesis and therapy. Adv Exp Med Biol 615:223–250PubMedCrossRefGoogle Scholar
  27. 27.
    Ben-Neriah Y, Karin M (2011) Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat Immunol 12(8):715–723PubMedCrossRefGoogle Scholar
  28. 28.
    Smale ST (2011) Hierarchies of NF-kappaB target-gene regulation. Nat Immunol 12(8):689–694PubMedCrossRefGoogle Scholar
  29. 29.
    Baud V, Karin M (2009) Is NF-kappaB a good target for cancer therapy? hopes and pitfalls. Nat Rev Drug Discov 8(1):33–40PubMedCrossRefGoogle Scholar
  30. 30.
    Karin M, Greten FR (2005) NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5(10):749–759PubMedCrossRefGoogle Scholar
  31. 31.
    Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H et al (2004) Gastric cancer originating from bone marrow-derived cells. Science 306(5701):1568–1571PubMedCrossRefGoogle Scholar
  32. 32.
    Bogdan C (2001) Nitric oxide and the immune response. Nat Immunol 2(10):907–916PubMedCrossRefGoogle Scholar
  33. 33.
    Bitton-Worms K, Pikarsky E, Aronheim A (2010) The AP-1 repressor protein, JDP2, potentiates hepatocellular carcinoma in mice. Mol Cancer 9:54PubMedCrossRefGoogle Scholar
  34. 34.
    Yang Q, Huang W, Jozwik C, Lin Y, Glasman M, Caohuy H et al (2005) Cardiac glycosides inhibit TNF-alpha/NF-kappaB signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor. Proc Natl Acad Sci USA 102(27):9631–9636PubMedCrossRefGoogle Scholar
  35. 35.
    Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22(2):231–237PubMedCrossRefGoogle Scholar
  36. 36.
    Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG et al (2008) Re-educating tumor-associated macrophages by targeting NF-kappaB. J Exp Med 205(6):1261–1268PubMedCrossRefGoogle Scholar
  37. 37.
    Yang HS, Jansen AP, Nair R, Shibahara K, Verma AK, Cmarik JL et al (2001) A novel transformation suppressor, Pdcd4, inhibits AP-1 transactivation but not NF-kappaB or ODC transactivation. Oncogene 20(6):669–676PubMedCrossRefGoogle Scholar
  38. 38.
    Bredel M, Scholtens DM, Yadav AK, Alvarez AA, Renfrow JJ, Chandler JP et al (2011) NFKBIA deletion in glioblastomas. N Engl J Med 364(7):627–637PubMedCrossRefGoogle Scholar
  39. 39.
    Ammirante M, Luo JL, Grivennikov S, Nedospasov S, Karin M (2010) B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464(7286):302–305PubMedCrossRefGoogle Scholar
  40. 40.
    Luo JL, Tan W, Ricono JM, Korchynskyi O, Zhang M, Gonias SL et al (2007) Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature 446(7136):690–694PubMedCrossRefGoogle Scholar
  41. 41.
    Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ et al (2007) Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 12(2):131–144PubMedCrossRefGoogle Scholar
  42. 42.
    Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P et al (2009) Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 69(4):1302–1313PubMedCrossRefGoogle Scholar
  43. 43.
    Merkhofer EC, Cogswell P, Baldwin AS (2010) Her2 Activates NF-kappaB and induces invasion through the canonical pathway involving IKKalpha. Oncogene 29(8):1238–1248PubMedCrossRefGoogle Scholar
  44. 44.
    Maeda S, Kamata H, Luo JL, Leffert H, Karin M (2005) IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121(7):977–990PubMedCrossRefGoogle Scholar
  45. 45.
    Arnott CH, Scott KA, Moore RJ, Robinson SC, Thompson RG, Balkwill FR (2004) Expression of both TNF-alpha receptor subtypes is essential for optimal skin tumour development. Oncogene 23(10):1902–1910PubMedCrossRefGoogle Scholar
  46. 46.
    Dajee M, Lazarov M, Zhang JY, Cai T, Green CL, Russell AJ et al (2003) NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421(6923): 639–643PubMedCrossRefGoogle Scholar
  47. 47.
    Lind MH, Rozell B, Wallin RP, van Hogerlinden M, Ljunggren HG, Toftgard R et al (2004) Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-kappaB inhibition. Proc Natl Acad Sci USA 101(14):4972–4977PubMedCrossRefGoogle Scholar
  48. 48.
    Korkaya H, Paulson A, Iovino F, Wicha MS (2008) HER2 Regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 27(47):6120–6130PubMedCrossRefGoogle Scholar
  49. 49.
    Liu M, Sakamaki T, Casimiro MC, Willmarth NE, Quong AA, Ju X et al (2010) The canonical NF-kappaB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion. Cancer Res 70(24):10464–10473PubMedCrossRefGoogle Scholar
  50. 50.
    Karin M, Yamamoto Y, Wang QM (2004) The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov 3(1):17–26PubMedCrossRefGoogle Scholar
  51. 51.
    Beyaert R, Cuenda A, Vanden Berghe W, Plaisance S, Lee JC, Haegeman G et al (1996) The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis response to tumor necrosis factor. EMBO J 15(8):1914–1923PubMedGoogle Scholar
  52. 52.
    Amschler K, Schon MP, Pletz N, Wallbrecht K, Erpenbeck L, Schon M (2010) NF-kappaB inhibition through proteasome inhibition or IKKbeta blockade increases the susceptibility of melanoma cells to cytostatic treatment through distinct pathways. J Invest Dermatol 130(4):1073–1086PubMedCrossRefGoogle Scholar
  53. 53.
    Wilken R, Veena MS, Wang MB, Srivatsan ES (2011) Curcumin: a review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol Cancer 10:12PubMedCrossRefGoogle Scholar
  54. 54.
    Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL et al (2008) Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 14(14):4491–4499PubMedCrossRefGoogle Scholar
  55. 55.
    Semenza GL (2009) HIF-1 inhibitors for cancer therapy: from gene expression to drug discovery. Curr Pharm Des 15(33):3839–3843PubMedCrossRefGoogle Scholar
  56. 56.
    Nizet V, Johnson RS (2009) Interdependence of hypoxic and innate immune responses. Nat Rev Immunol 9(9):609–617PubMedCrossRefGoogle Scholar
  57. 57.
    Melillo G (2011) Hypoxia: jump-starting inflammation. Blood 117(9):2561–2562PubMedCrossRefGoogle Scholar
  58. 58.
    Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T et al (2005) Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med 201(1):105–115PubMedCrossRefGoogle Scholar
  59. 59.
    Taylor CT, Cummins EP (2009) The role of NF-kappaB in hypoxia-induced gene expression. Ann N Y Acad Sci 1177:178–184PubMedCrossRefGoogle Scholar
  60. 60.
    Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V et al (2008) NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 453(7196):807–811PubMedCrossRefGoogle Scholar
  61. 61.
    Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F et al (2006) Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci USA 103(48):18154–18159PubMedCrossRefGoogle Scholar
  62. 62.
    Taylor CT (2008) Interdependent roles for hypoxia inducible factor and nuclear factor-kappaB in hypoxic inflammation. J Physiol 586(Pt 17):4055–4059PubMedCrossRefGoogle Scholar
  63. 63.
    Belaiba RS, Bonello S, Zahringer C, Schmidt S, Hess J, Kietzmann T et al (2007) Hypoxia up-regulates hypoxia-inducible factor-1alpha transcription by involving phosphatidylinositol 3-kinase and nuclear factor kappaB in pulmonary artery smooth muscle cells. Mol Biol Cell 18(12):4691–4697PubMedCrossRefGoogle Scholar
  64. 64.
    van Uden P, Kenneth NS, Rocha S (2008) Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochem J 412(3):477–484PubMedCrossRefGoogle Scholar
  65. 65.
    Scortegagna M, Cataisson C, Martin RJ, Hicklin DJ, Schreiber RD, Yuspa SH et al (2008) HIF-1alpha regulates epithelial inflammation by cell autonomous NFkappaB activation and paracrine stromal remodeling. Blood 111(7):3343–3354PubMedCrossRefGoogle Scholar
  66. 66.
    Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ et al (1987) Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell 49(6):729–739PubMedCrossRefGoogle Scholar
  67. 67.
    Angel P, Karin M (1991) The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1072(2–3):129–157PubMedGoogle Scholar
  68. 68.
    Halazonetis TD, Georgopoulos K, Greenberg ME, Leder P (1988) c-Jun dimerizes with itself and with c-Fos, forming complexes of different DNA binding affinities. Cell 55(5):917–924PubMedCrossRefGoogle Scholar
  69. 69.
    Kouzarides T, Ziff E (1988) The role of the leucine zipper in the fos-jun interaction. Nature 336(6200):646–651PubMedCrossRefGoogle Scholar
  70. 70.
    Kataoka K, Noda M, Nishizawa M (1994) Maf nuclear oncoprotein recognizes sequences related to an AP-1 site and forms heterodimers with both Fos and Jun. Mol Cell Biol 14(1):700–712PubMedGoogle Scholar
  71. 71.
    Wisdom R (1999) AP-1: one switch for many signals. Exp Cell Res 253(1):180–185PubMedCrossRefGoogle Scholar
  72. 72.
    Karin M, Liu Z, Zandi E (1997) AP-1 function and regulation. Curr Opin Cell Biol 9(2):240–246PubMedCrossRefGoogle Scholar
  73. 73.
    Fujiwara KT, Kataoka K, Nishizawa M (1993) Two new members of the maf oncogene family, mafK and mafF, encode nuclear b-Zip proteins lacking putative trans-activator domain. Oncogene 8(9):2371–2380PubMedGoogle Scholar
  74. 74.
    Landschulz WH, Johnson PF, McKnight SL (1988) The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science 240(4860):1759–1764PubMedCrossRefGoogle Scholar
  75. 75.
    Wagner EF, Schonthaler HB, Guinea-Viniegra J, Tschachler E (2010) Psoriasis: what we have learned from mouse models. Nat Rev Rheumatol 6(12):704–714PubMedCrossRefGoogle Scholar
  76. 76.
    Schutte J, Minna JD, Birrer MJ (1989) Deregulated expression of human c-jun transforms primary rat embryo cells in cooperation with an activated c-Ha-ras gene and transforms rat-1a cells as a single gene. Proc Natl Acad Sci USA 86(7):2257–2261PubMedCrossRefGoogle Scholar
  77. 77.
    Schutte J, Viallet J, Nau M, Segal S, Fedorko J, Minna J (1989) Jun-B inhibits and c-fos stimulates the transforming and trans-activating activities of c-jun. Cell 59(6):987–997PubMedCrossRefGoogle Scholar
  78. 78.
    Pfarr CM, Mechta F, Spyrou G, Lallemand D, Carillo S, Yaniv M (1994) Mouse JunD negatively regulates fibroblast growth and antagonizes transformation by ras. Cell 76(4):747–760PubMedCrossRefGoogle Scholar
  79. 79.
    Passegue E, Wagner EF (2000) JunB suppresses cell proliferation by transcriptional activation of p16 (INK4a) expression. EMBO J 19(12):2969–2979PubMedCrossRefGoogle Scholar
  80. 80.
    Chiu R, Angel P, Karin M (1989) Jun-B differs in its biological properties from, and is a negative regulator of, c-Jun. Cell 59(6):979–986PubMedCrossRefGoogle Scholar
  81. 81.
    Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410(6824):37–40PubMedCrossRefGoogle Scholar
  82. 82.
    Matthews CP, Colburn NH, Young MR (2007) AP-1 a target for cancer prevention. Curr Cancer Drug Targets 7(4):317–324PubMedCrossRefGoogle Scholar
  83. 83.
    Whitmarsh AJ, Davis RJ (1996) Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med (Berl) 74(10):589–607CrossRefGoogle Scholar
  84. 84.
    Dong Z, Birrer MJ, Watts RG, Matrisian LM, Colburn NH (1994) Blocking of tumor promoter-induced AP-1 activity inhibits induced transformation in JB6 mouse epidermal cells. Proc Natl Acad Sci USA 91(2):609–613PubMedCrossRefGoogle Scholar
  85. 85.
    Angel P, Hattori K, Smeal T, Karin M (1988) The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell 55(5):875–885PubMedCrossRefGoogle Scholar
  86. 86.
    Gonzalez JM, Navarro-Puche A, Casar B, Crespo P, Andres V (2008) Fast regulation of AP-1 activity through interaction of lamin A/C, ERK1/2, and c-Fos at the nuclear envelope. J Cell Biol 183(4):653–666PubMedCrossRefGoogle Scholar
  87. 87.
    Ellenberger TE, Brandl CJ, Struhl K, Harrison SC (1992) The GCN4 basic region leucine zipper binds DNA as a dimer of uninterrupted alpha helices: crystal structure of the protein-DNA complex. Cell 71(7):1223–1237PubMedCrossRefGoogle Scholar
  88. 88.
    Schumacher MA, Goodman RH, Brennan RG (2000) The structure of a CREB bZIP.Somatostatin CRE complex reveals the basis for selective dimerization and divalent cation-enhanced DNA binding. J Biol Chem 275(45):35242–35247PubMedCrossRefGoogle Scholar
  89. 89.
    Zenz R, Eferl R, Scheinecker C, Redlich K, Smolen J, Schonthaler HB et al (2008) Activator protein 1 (Fos/Jun) functions in inflammatory bone and skin disease. Arthritis Res Ther 10(1):201PubMedCrossRefGoogle Scholar
  90. 90.
    Karin M (1995) The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem 270(28):16483–16486PubMedGoogle Scholar
  91. 91.
    van Dam H, Castellazzi M (2001) Distinct roles of Jun : Fos and Jun : ATF dimers in oncogenesis. Oncogene 20(19):2453–2464PubMedCrossRefGoogle Scholar
  92. 92.
    Baan B, Pardali E, ten Dijke P, van Dam H (2010) In situ proximity ligation detection of c-Jun/AP-1 dimers reveals increased levels of c-Jun/Fra1 complexes in aggressive breast cancer cell lines in vitro and in vivo. Mol Cell Proteomics 9(9):1982–1990PubMedCrossRefGoogle Scholar
  93. 93.
    Ryseck RP, Bravo R (1991) c-JUN, JUN B, and JUN D differ in their binding affinities to AP-1 and CRE consensus sequences: effect of FOS proteins. Oncogene 6(4):533–542PubMedGoogle Scholar
  94. 94.
    Leaner VD, Donninger H, Birrer MJ (2007) Transcription factors as targets for cancer therapy: AP-1 a potential therapeutic target, in Current Cancer Therapy Reviews. Bentham Science Publishers, pp 1–6Google Scholar
  95. 95.
    Eferl R, Wagner EF (2003) AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3(11):859–868PubMedCrossRefGoogle Scholar
  96. 96.
    Karin M, Delhase M (1998) JNK or IKK, AP-1 or NF-kappaB, which are the targets for MEK kinase 1 action? Proc Natl Acad Sci USA 95(16):9067–9069PubMedCrossRefGoogle Scholar
  97. 97.
    Smeal T, Binetruy B, Mercola D, Grover-Bardwick A, Heidecker G, Rapp UR et al (1992) Oncoprotein-mediated signalling cascade stimulates c-Jun activity by phosphorylation of serines 63 and 73. Mol Cell Biol 12(8):3507–3513PubMedGoogle Scholar
  98. 98.
    Black EJ, Clair T, Delrow J, Neiman P, Gillespie DA (2004) Microarray analysis identifies autotaxin, a tumour cell motility and angiogenic factor with lysophospholipase D activity, as a specific target of cell transformation by v-Jun. Oncogene 23(13):2357–2366PubMedCrossRefGoogle Scholar
  99. 99.
    Bos TJ, Margiotta P, Bush L, Wasilenko W (1999) Enhanced cell motility and invasion of chicken embryo fibroblasts in response to Jun over-expression. Int J Cancer 81(3):404–410PubMedCrossRefGoogle Scholar
  100. 100.
    Briggs J, Chamboredon S, Castellazzi M, Kerry JA, Bos TJ (2002) Transcriptional upregulation of SPARC, in response to c-Jun overexpression, contributes to increased motility and invasion of MCF7 breast cancer cells. Oncogene 21(46):7077–7091PubMedCrossRefGoogle Scholar
  101. 101.
    el Bahassi M, Karyala S, Tomlinson CR, Sartor MA, Medvedovic M, Hennigan RF (2004) Critical regulation of genes for tumor cell migration by AP-1. Clin Exp Metastasis 21(4):293–304CrossRefGoogle Scholar
  102. 102.
    Cohen SB, Waha A, Gelman IH, Vogt PK (2001) Expression of a down-regulated target, SSeCKS, reverses v-Jun-induced transformation of 10 T1/2 murine fibroblasts. Oncogene 20(2):141–146PubMedCrossRefGoogle Scholar
  103. 103.
    McGarry LC, Winnie JN, Ozanne BW (2004) Invasion of v-Fos(FBR)-transformed cells is dependent upon histone deacetylase activity and suppression of histone deacetylase regulated genes. Oncogene 23(31):5284–5292PubMedCrossRefGoogle Scholar
  104. 104.
    Young MR, Li JJ, Rincon M, Flavell RA, Sathyanarayana BK, Hunziker R et al (1999) Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. Proc Natl Acad Sci USA 96(17):9827–9832PubMedCrossRefGoogle Scholar
  105. 105.
    Dikshit B, Irshad K, Madan E, Aggarwal N, Sarkar C, Chandra PS et al (2012) FAT1 acts as an upstream regulator of oncogenic and inflammatory pathways, via PDCD4, in glioma cells. OncogeneGoogle Scholar
  106. 106.
    Shaulian E (2010) AP-1–the Jun proteins: oncogenes or tumor suppressors in disguise? Cell Signal 22(6):894–899PubMedCrossRefGoogle Scholar
  107. 107.
    Dahlman-Wright K, Qiao Y, Jonsson P, Gustafsson JA, Williams C, Zhao C (2012) Interplay between AP-1 and estrogen receptor alpha in regulating gene expression and proliferation networks in breast cancer cells. Carcinogenesis 33(9):1684–1691PubMedCrossRefGoogle Scholar
  108. 108.
    Milde-Langosch K, Janke S, Wagner I, Schroder C, Streichert T, Bamberger AM et al (2008) Role of Fra-2 in breast cancer: influence on tumor cell invasion and motility. Breast Cancer Res Treat 107(3):337–347PubMedCrossRefGoogle Scholar
  109. 109.
    Milde-Langosch K, Roder H, Andritzky B, Aslan B, Hemminger G, Brinkmann A et al (2004) The role of the AP-1 transcription factors c-Fos, FosB, Fra-1 and Fra-2 in the invasion process of mammary carcinomas. Breast Cancer Res Treat 86(2):139–152PubMedCrossRefGoogle Scholar
  110. 110.
    Kajanne R, Miettinen P, Tenhunen M, Leppa S (2009) Transcription factor AP-1 promotes growth and radioresistance in prostate cancer cells. Int J Oncol 35(5):1175–1182PubMedGoogle Scholar
  111. 111.
    Parra E, Ferreira J, Ortega A (2011) Overexpression of EGR-1 modulates the activity of NF-kappaB and AP-1 in prostate carcinoma PC-3 and LNCaP cell lines. Int J Oncol 39(2):345–352PubMedGoogle Scholar
  112. 112.
    Domann FE, Levy JP, Birrer MJ, Bowden GT (1994) Stable expression of a c-JUN deletion mutant in two malignant mouse epidermal cell lines blocks tumor formation in nude mice. Cell Growth Differ 5(1):9–16PubMedGoogle Scholar
  113. 113.
    Dong Z, Crawford HC, Lavrovsky V, Taub D, Watts R, Matrisian LM et al (1997) A dominant negative mutant of jun blocking 12-O-tetradecanoylphorbol-13-acetate-induced invasion in mouse keratinocytes. Mol Carcinog 19(3):204–212PubMedCrossRefGoogle Scholar
  114. 114.
    Zhang HS, Yan B, Li XB, Fan L, Zhang YF, Wu GH, et al (2012) Pax2 induces expression of cyclin D1 through activating AP-1 and promotes proliferation of colon cancer cells. J Biol Chem 287(53):44164–44172Google Scholar
  115. 115.
    Saez E, Rutberg SE, Mueller E, Oppenheim H, Smoluk J, Yuspa SH et al (1995) c-fos is required for malignant progression of skin tumors. Cell 82(5):721–732PubMedCrossRefGoogle Scholar
  116. 116.
    Miller AD, Curran T, Verma IM (1984) c-fos protein can induce cellular transformation: a novel mechanism of activation of a cellular oncogene. Cell 36(1):51–60PubMedCrossRefGoogle Scholar
  117. 117.
    Bos TJ, Monteclaro FS, Mitsunobu F, Ball AR Jr, Chang CH, Nishimura T et al (1990) Efficient transformation of chicken embryo fibroblasts by c-Jun requires structural modification in coding and noncoding sequences. Genes Dev 4(10):1677–1687PubMedCrossRefGoogle Scholar
  118. 118.
    Yoshida T, Shindo Y, Ohta K, Iba H (1989) Identification of a small region of the v-fos gene product that is sufficient for transforming potential and growth-stimulating activity. Oncogene Res 5(2):79–89PubMedGoogle Scholar
  119. 119.
    Xie W, Herschman HR (1995) v-src induces prostaglandin synthase 2 gene expression by activation of the c-Jun N-terminal kinase and the c-Jun transcription factor. J Biol Chem 270(46):27622–27628PubMedCrossRefGoogle Scholar
  120. 120.
    Meixner A, Karreth F, Kenner L, Wagner EF (2004) JunD regulates lymphocyte proliferation and T helper cell cytokine expression. EMBO J 23(6):1325–1335PubMedCrossRefGoogle Scholar
  121. 121.
    Wagner EF, Eferl R (2005) Fos/AP-1 proteins in bone and the immune system. Immunol Rev 208:126–140PubMedCrossRefGoogle Scholar
  122. 122.
    Hasselblatt P, Gresh L, Kudo H, Guinea-Viniegra J, Wagner EF (2008) The role of the transcription factor AP-1 in colitis-associated and beta-catenin-dependent intestinal tumorigenesis in mice. Oncogene 27(47):6102–6109PubMedCrossRefGoogle Scholar
  123. 123.
    Kim MK, Kim K, Han JY, Lim JM, Song YS (2011) Modulation of inflammatory signaling pathways by phytochemicals in ovarian cancer. Genes Nutr 6(2):109–115PubMedCrossRefGoogle Scholar
  124. 124.
    Li JJ, Rhim JS, Schlegel R, Vousden KH, Colburn NH (1998) Expression of dominant negative Jun inhibits elevated AP-1 and NF-kappaB transactivation and suppresses anchorage independent growth of HPV immortalized human keratinocytes. Oncogene 16(21):2711–2721PubMedCrossRefGoogle Scholar
  125. 125.
    Ondrey FG, Dong G, Sunwoo J, Chen Z, Wolf JS, Crowl-Bancroft CV et al (1999) Constitutive activation of transcription factors NF-(kappa)B, AP-1, and NF-IL6 in human head and neck squamous cell carcinoma cell lines that express pro-inflammatory and pro-angiogenic cytokines. Mol Carcinog 26(2):119–129PubMedCrossRefGoogle Scholar
  126. 126.
    Wolf JS, Chen Z, Dong G, Sunwoo JB, Bancroft CC, Capo DE et al (2001) IL (interleukin)-1alpha promotes nuclear factor-kappaB and AP-1-induced IL-8 expression, cell survival, and proliferation in head and neck squamous cell carcinomas. Clin Cancer Res 7(6):1812–1820PubMedGoogle Scholar
  127. 127.
    Wang Q, Zhang Y, Yang HS (2012) Pdcd4 knockdown up-regulates MAP4K1 expression and activation of AP-1 dependent transcription through c-Myc. Biochim Biophys Acta 1823(10):1807–1814PubMedCrossRefGoogle Scholar
  128. 128.
    Yang HS, Knies JL, Stark C, Colburn NH (2003) Pdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation. Oncogene 22(24):3712–3720PubMedCrossRefGoogle Scholar
  129. 129.
    Yang HS, Matthews CP, Clair T, Wang Q, Baker AR, Li CC et al (2006) Tumorigenesis suppressor Pdcd4 down-regulates mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion. Mol Cell Biol 26(4):1297–1306PubMedCrossRefGoogle Scholar
  130. 130.
    Azzoni L, Zatsepina O, Abebe B, Bennett IM, Kanakaraj P, Perussia B (1998) Differential transcriptional regulation of CD161 and a novel gene, 197/15a, by IL-2, IL-15, and IL-12 in NK and T cells. J Immunol 161(7):3493–3500PubMedGoogle Scholar
  131. 131.
    Zhang Z, DuBois RN (2001) Detection of differentially expressed genes in human colon carcinoma cells treated with a selective COX-2 inhibitor. Oncogene 20(33):4450–4456PubMedCrossRefGoogle Scholar
  132. 132.
    Subbaramaiah K, Cole PA, Dannenberg AJ (2002) Retinoids and carnosol suppress cyclooxygenase-2 transcription by CREB-binding protein/p300-dependent and -independent mechanisms. Cancer Res 62(9):2522–2530PubMedGoogle Scholar
  133. 133.
    Subbaramaiah K, Norton L, Gerald W, Dannenberg AJ (2002) Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3. J Biol Chem 277(21):18649–18657PubMedCrossRefGoogle Scholar
  134. 134.
    Trifan OC, Hla T (2003) Cyclooxygenase-2 modulates cellular growth and promotes tumorigenesis. J Cell Mol Med 7(3):207–222PubMedCrossRefGoogle Scholar
  135. 135.
    Dempke W, Rie C, Grothey A, Schmoll HJ (2001) Cyclooxygenase-2: a novel target for cancer chemotherapy? J Cancer Res Clin Oncol 127(7):411–417PubMedCrossRefGoogle Scholar
  136. 136.
    Hilger-Eversheim K, Moser M, Schorle H, Buettner R (2000) Regulatory roles of AP-2 transcription factors in vertebrate development, apoptosis and cell-cycle control. Gene 260(1–2):1–12PubMedCrossRefGoogle Scholar
  137. 137.
    Orso F, Penna E, Cimino D, Astanina E, Maione F, Valdembri D et al (2008) AP-2alpha and AP-2gamma regulate tumor progression via specific genetic programs. FASEB J 22(8):2702–2714PubMedCrossRefGoogle Scholar
  138. 138.
    Bosher JM, Williams T, Hurst HC (1995) The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 overexpression in human mammary carcinoma. Proc Natl Acad Sci USA 92(3):744–747PubMedCrossRefGoogle Scholar
  139. 139.
    Gilbertson RJ, Perry RH, Kelly PJ, Pearson AD, Lunec J (1997) Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. Cancer Res 57(15):3272–3280PubMedGoogle Scholar
  140. 140.
    Gee JM, Robertson JF, Ellis IO, Nicholson RI, Hurst HC (1999) Immunohistochemical analysis reveals a tumour suppressor-like role for the transcription factor AP-2 in invasive breast cancer. J Pathol 189(4):514–520PubMedCrossRefGoogle Scholar
  141. 141.
    Karjalainen JM, Kellokoski JK, Eskelinen MJ, Alhava EM, Kosma VM (1998) Downregulation of transcription factor AP-2 predicts poor survival in stage I cutaneous malignant melanoma. J Clin Oncol 16(11):3584–3591PubMedGoogle Scholar
  142. 142.
    Pellikainen J, Kataja V, Ropponen K, Kellokoski J, Pietilainen T, Bohm J et al (2002) Reduced nuclear expression of transcription factor AP-2 associates with aggressive breast cancer. Clin Cancer Res 8(11):3487–3495PubMedGoogle Scholar
  143. 143.
    Ropponen KM, Kellokoski JK, Pirinen RT, Moisio KI, Eskelinen MJ, Alhava EM et al (2001) Expression of transcription factor AP-2 in colorectal adenomas and adenocarcinomas; comparison of immunohistochemistry and in situ hybridisation. J Clin Pathol 54(7):533–538PubMedCrossRefGoogle Scholar
  144. 144.
    Ruiz M, Troncoso P, Bruns C, Bar-Eli M (2001) Activator protein 2alpha transcription factor expression is associated with luminal differentiation and is lost in prostate cancer. Clin Cancer Res 7(12):4086–4095PubMedGoogle Scholar
  145. 145.
    Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264(5164):1415–1421PubMedCrossRefGoogle Scholar
  146. 146.
    Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T et al (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77(1):63–71PubMedCrossRefGoogle Scholar
  147. 147.
    Zhang T, Kee WH, Seow KT, Fung W, Cao X (2000) The coiled-coil domain of Stat3 is essential for its SH2 domain-mediated receptor binding and subsequent activation induced by epidermal growth factor and interleukin-6. Mol Cell Biol 20(19):7132–7139PubMedCrossRefGoogle Scholar
  148. 148.
    Sadowski HB, Shuai K, Darnell JE, Gilman MZ Jr (1993) A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. Science 261(5129):1739–1744PubMedCrossRefGoogle Scholar
  149. 149.
    Zhong Z, Wen Z, Darnell JE Jr (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264(5155):95–98PubMedCrossRefGoogle Scholar
  150. 150.
    Stahl N, Boulton TG, Farruggella T, Ip NY, Davis S, Witthuhn BA et al (1994) Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science 263(5143):92–95PubMedCrossRefGoogle Scholar
  151. 151.
    Lutticken C, Wegenka UM, Yuan J, Buschmann J, Schindler C, Ziemiecki A et al (1994) Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science 263(5143):89–92PubMedCrossRefGoogle Scholar
  152. 152.
    Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE Jr (1994) Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell 76(5):821–828PubMedCrossRefGoogle Scholar
  153. 153.
    Shain KH, Yarde DN, Meads MB, Huang M, Jove R, Hazlehurst LA et al (2009) Beta1 integrin adhesion enhances IL-6-mediated STAT3 signaling in myeloma cells: implications for microenvironment influence on tumor survival and proliferation. Cancer Res 69(3):1009–1015PubMedCrossRefGoogle Scholar
  154. 154.
    Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C et al (1999) Stat3 as an oncogene. Cell 98(3):295–303PubMedCrossRefGoogle Scholar
  155. 155.
    Vignais ML, Sadowski HB, Watling D, Rogers NC, Gilman M (1996) Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins. Mol Cell Biol 16(4):1759–1769PubMedGoogle Scholar
  156. 156.
    Giordano V, De Falco G, Chiari R, Quinto I, Pelicci PG, Bartholomew L et al (1997) Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase. J Immunol 158(9):4097–4103PubMedGoogle Scholar
  157. 157.
    Arredondo J, Chernyavsky AI, Jolkovsky DL, Pinkerton KE, Grando SA (2006) Receptor-mediated tobacco toxicity: cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of alpha7 nicotinic receptor in oral keratinocytes. FASEB J 20(12):2093–2101PubMedCrossRefGoogle Scholar
  158. 158.
    Chauhan D, Li G, Podar K, Hideshima T, Neri P, He D et al (2005) A novel carbohydrate-based therapeutic GCS-100 overcomes bortezomib resistance and enhances dexamethasone-induced apoptosis in multiple myeloma cells. Cancer Res 65(18):8350–8358PubMedCrossRefGoogle Scholar
  159. 159.
    Tharappel JC, Lee EY, Robertson LW, Spear BT, Glauert HP (2002) Regulation of cell proliferation, apoptosis, and transcription factor activities during the promotion of liver carcinogenesis by polychlorinated biphenyls. Toxicol Appl Pharmacol 179(3):172–184PubMedCrossRefGoogle Scholar
  160. 160.
    Megeney LA, Perry RL, LeCouter JE, Rudnicki MA (1996) bFGF and LIF signaling activates STAT3 in proliferating myoblasts. Dev Genet 19(2):139–145PubMedCrossRefGoogle Scholar
  161. 161.
    Garcia R, Yu CL, Hudnall A, Catlett R, Nelson KL, Smithgall T et al (1997) Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Differ 8(12):1267–1276PubMedGoogle Scholar
  162. 162.
    Migone TS, Lin JX, Cereseto A, Mulloy JC, O’Shea JJ, Franchini G et al (1995) Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I. Science 269(5220):79–81PubMedCrossRefGoogle Scholar
  163. 163.
    Tian SS, Tapley P, Sincich C, Stein RB, Rosen J, Lamb P (1996) Multiple signaling pathways induced by granulocyte colony-stimulating factor involving activation of JAKs, STAT5, and/or STAT3 are required for regulation of three distinct classes of immediate early genes. Blood 88(12):4435–4444PubMedGoogle Scholar
  164. 164.
    Fu AK, Fu WY, Ng AK, Chien WW, Ng YP, Wang JH et al (2004) Cyclin-dependent kinase 5 phosphorylates signal transducer and activator of transcription 3 and regulates its transcriptional activity. Proc Natl Acad Sci USA 101(17):6728–6733PubMedCrossRefGoogle Scholar
  165. 165.
    Wen Z, Darnell JE Jr (1997) Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence on DNA binding of Stat1 and Stat3. Nucleic Acids Res 25(11):2062–2067PubMedCrossRefGoogle Scholar
  166. 166.
    Jain N, Zhang T, Kee WH, Li W, Cao X (1999) Protein kinase C delta associates with and phosphorylates Stat3 in an interleukin-6-dependent manner. J Biol Chem 274(34): 24392–24400PubMedCrossRefGoogle Scholar
  167. 167.
    Aziz MH, Manoharan HT, Church DR, Dreckschmidt NE, Zhong W, Oberley TD et al (2007) Protein kinase Cepsilon interacts with signal transducers and activators of transcription 3 (Stat3), phosphorylates Stat3Ser727, and regulates its constitutive activation in prostate cancer. Cancer Res 67(18):8828–8838PubMedCrossRefGoogle Scholar
  168. 168.
    Yokogami K, Wakisaka S, Avruch J, Reeves SA (2000) Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR. Curr Biol 10(1):47–50PubMedCrossRefGoogle Scholar
  169. 169.
    Brantley EC, Benveniste EN (2008) Signal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas. Mol Cancer Res 6(5):675–684PubMedCrossRefGoogle Scholar
  170. 170.
    Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809PubMedCrossRefGoogle Scholar
  171. 171.
    Yuan ZL, Guan YJ, Chatterjee D, Chin YE (2005) Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307(5707):269–273PubMedCrossRefGoogle Scholar
  172. 172.
    Pfitzner E, Kliem S, Baus D, Litterst CM (2004) The role of STATs in inflammation and inflammatory diseases. Curr Pharm Des 10(23):2839–2850PubMedCrossRefGoogle Scholar
  173. 173.
    Dalwadi H, Krysan K, Heuze-Vourc’h N, Dohadwala M, Elashoff D, Sharma S et al (2005) Cyclooxygenase-2-dependent activation of signal transducer and activator of transcription 3 by interleukin-6 in non-small cell lung cancer. Clin Cancer Res 11(21):7674–7682PubMedCrossRefGoogle Scholar
  174. 174.
    Ernst M, Najdovska M, Grail D, Lundgren-May T, Buchert M, Tye H et al (2008) STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J Clin Invest 118(5):1727–1738PubMedGoogle Scholar
  175. 175.
    Kobierski LA, Srivastava S, Borsook D (2000) Systemic lipopolysaccharide and interleukin-1beta activate the interleukin 6: STAT intracellular signaling pathway in neurons of mouse trigeminal ganglion. Neurosci Lett 281(1):61–64PubMedCrossRefGoogle Scholar
  176. 176.
    Frank DA (2007) STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett 251(2):199–210PubMedCrossRefGoogle Scholar
  177. 177.
    Bromberg JF, Horvath CM, Besser D, Lathem WW Jr, Darnell JE Jr (1998) Stat3 activation is required for cellular transformation by v-src. Mol Cell Biol 18(5):2553–2558PubMedGoogle Scholar
  178. 178.
    Yu Z, Zhang W, Kone BC (2002) Signal transducers and activators of transcription 3 (STAT3) inhibits transcription of the inducible nitric oxide synthase gene by interacting with nuclear factor kappaB. Biochem J 367(Pt 1):97–105PubMedCrossRefGoogle Scholar
  179. 179.
    Rahaman SO, Harbor PC, Chernova O, Barnett GH, Vogelbaum MA, Haque SJ (2002) Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene 21(55):8404–8413PubMedCrossRefGoogle Scholar
  180. 180.
    Atkinson GP, Nozell SE, Benveniste ET (2010) NF-kappaB and STAT3 signaling in glioma: targets for future therapies. Expert Rev Neurother 10(4):575–586Google Scholar
  181. 181.
    Yu H, Jove R (2004) The STATs of cancer–new molecular targets come of age. Nat Rev Cancer 4(2):97–105PubMedCrossRefGoogle Scholar
  182. 182.
    Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R et al (1999) Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10(1):105–115PubMedCrossRefGoogle Scholar
  183. 183.
    Karni R, Jove R, Levitzki A (1999) Inhibition of pp 60c-Src reduces Bcl-XL expression and reverses the transformed phenotype of cells overexpressing EGF and HER-2 receptors. Oncogene 18(33):4654–4662PubMedCrossRefGoogle Scholar
  184. 184.
    Zushi S, Shinomura Y, Kiyohara T, Miyazaki Y, Kondo S, Sugimachi M et al (1998) STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells. Int J Cancer 78(3):326–330PubMedCrossRefGoogle Scholar
  185. 185.
    Mahboubi K, Li F, Plescia J, Kirkiles-Smith NC, Mesri M, Du Y et al (2001) Interleukin-11 up-regulates survivin expression in endothelial cells through a signal transducer and activator of transcription-3 pathway. Lab Invest 81(3):327–334PubMedCrossRefGoogle Scholar
  186. 186.
    Liu H, Ma Y, Cole SM, Zander C, Chen KH, Karras J et al (2003) Serine phosphorylation of STAT3 is essential for Mcl-1 expression and macrophage survival. Blood 102(1):344–352PubMedCrossRefGoogle Scholar
  187. 187.
    Bhattacharya S, Schindler C (2003) Regulation of Stat3 nuclear export. J Clin Invest 111(4):553–559PubMedGoogle Scholar
  188. 188.
    Masuda M, Suzui M, Yasumatu R, Nakashima T, Kuratomi Y, Azuma K et al (2002) Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res 62(12):3351–3355PubMedGoogle Scholar
  189. 189.
    Kiuchi N, Nakajima K, Ichiba M, Fukada T, Narimatsu M, Mizuno K et al (1999) STAT3 is required for the gp130-mediated full activation of the c-myc gene. J Exp Med 189(1): 63–73PubMedCrossRefGoogle Scholar
  190. 190.
    Shirogane T, Fukada T, Muller JM, Shima DT, Hibi M, Hirano T (1999) Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity 11(6):709–719PubMedCrossRefGoogle Scholar
  191. 191.
    Konnikova L, Kotecki M, Kruger MM, Cochran BH (2003) Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells. BMC Cancer 3:23PubMedCrossRefGoogle Scholar
  192. 192.
    Ivanov VN, Bhoumik A, Krasilnikov M, Raz R, Owen-Schaub LB, Levy D et al (2001) Cooperation between STAT3 and c-jun suppresses Fas transcription. Mol Cell 7(3):517–528PubMedCrossRefGoogle Scholar
  193. 193.
    Itoh M, Murata T, Suzuki T, Shindoh M, Nakajima K, Imai K et al (2006) Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells. Oncogene 25(8):1195–1204PubMedCrossRefGoogle Scholar
  194. 194.
    Gaemers IC, Vos HL, Volders HH, van der Valk SW, Hilkens J (2001) A stat-responsive element in the promoter of the episialin/MUC1 gene is involved in its overexpression in carcinoma cells. J Biol Chem 276(9):6191–6199PubMedCrossRefGoogle Scholar
  195. 195.
    Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J et al (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21(13):2000–2008PubMedCrossRefGoogle Scholar
  196. 196.
    Senft C, Polacin M, Priester M, Seifert V, Kogel D, Weissenberger J (2010) The nontoxic natural compound Curcumin exerts anti-proliferative, anti-migratory, and anti-invasive properties against malignant gliomas. BMC Cancer 10:491PubMedCrossRefGoogle Scholar
  197. 197.
    Cheng GZ, Zhang WZ, Sun M, Wang Q, Coppola D, Mansour M et al (2008) Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. J Biol Chem 283(21):14665–14673PubMedCrossRefGoogle Scholar
  198. 198.
    Wang Q, Sun Z, Yang HS (2008) Downregulation of tumor suppressor Pdcd4 promotes invasion and activates both beta-catenin/Tcf and AP-1-dependent transcription in colon carcinoma cells. Oncogene 27(11):1527–1535PubMedCrossRefGoogle Scholar
  199. 199.
    Sullivan NJ, Sasser AK, Axel AE, Vesuna F, Raman V, Ramirez N et al (2009) Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 28(33):2940–2947PubMedCrossRefGoogle Scholar
  200. 200.
    Nagpal JK, Mishra R, Das BR (2002) Activation of Stat-3 as one of the early events in tobacco chewing-mediated oral carcinogenesis. Cancer 94(9):2393–2400PubMedCrossRefGoogle Scholar
  201. 201.
    Boehm AL, Sen M, Seethala R, Gooding WE, Freilino M, Wong SM et al (2008) Combined targeting of epidermal growth factor receptor, signal transducer and activator of transcription-3, and Bcl-X(L) enhances antitumor effects in squamous cell carcinoma of the head and neck. Mol Pharmacol 73(6):1632–1642PubMedCrossRefGoogle Scholar
  202. 202.
    Rebouissou S, Amessou M, Couchy G, Poussin K, Imbeaud S, Pilati C et al (2009) Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 457(7226):200–204PubMedCrossRefGoogle Scholar
  203. 203.
    Kim G, Khanal P, Lim SC, Yun HJ, Ahn SG, Ki SH et al (2013) Interleukin-17 induces AP-1 activity and cellular transformation via upregulation of tumor progression locus 2 activity. Carcinogenesis 34(2):341–350Google Scholar
  204. 204.
    Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL et al (2007) Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest 117(12):3846–3856PubMedCrossRefGoogle Scholar
  205. 205.
    Bharti AC, Shishodia S, Reuben JM, Weber D, Alexanian R, Raj-Vadhan S et al (2004) Nuclear factor-kappaB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis. Blood 103(8):3175–3184PubMedCrossRefGoogle Scholar
  206. 206.
    Riehle KJ, Campbell JS, McMahan RS, Johnson MM, Beyer RP, Bammler TK et al (2008) Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3. J Exp Med 205(1):91–103PubMedCrossRefGoogle Scholar
  207. 207.
    von Knethen A, Callsen D, Brune B (1999) NF-kappaB and AP-1 activation by nitric oxide attenuated apoptotic cell death in RAW 264.7 macrophages. Mol Biol Cell 10(2):361–372CrossRefGoogle Scholar
  208. 208.
    Yin MJ, Yamamoto Y, Gaynor RB (1998) The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 396(6706):77–80PubMedCrossRefGoogle Scholar
  209. 209.
    Wahl C, Liptay S, Adler G, Schmid RM (1998) Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B. J Clin Invest 101(5):1163–1174PubMedCrossRefGoogle Scholar
  210. 210.
    Weber CK, Liptay S, Wirth T, Adler G, Schmid RM (2000) Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. Gastroenterology 119(5):1209–1218PubMedCrossRefGoogle Scholar
  211. 211.
    Egan LJ, Mays DC, Huntoon CJ, Bell MP, Pike MG, Sandborn WJ et al (1999) Inhibition of interleukin-1-stimulated NF-kappaB RelA/p65 phosphorylation by mesalamine is accompanied by decreased transcriptional activity. J Biol Chem 274(37):26448–26453PubMedCrossRefGoogle Scholar
  212. 212.
    Manna SK, Sah NK, Newman RA, Cisneros A, Aggarwal BB (2000) Oleandrin suppresses activation of nuclear transcription factor-kappaB, activator protein-1, and c-Jun NH2-terminal kinase. Cancer Res 60(14):3838–3847PubMedGoogle Scholar
  213. 213.
    Mijatovic T, Op De Beeck A, Van Quaquebeke E, Dewelle J, Darro F, de Launoi Y et al (2006) The cardenolide UNBS1450 is able to deactivate nuclear factor kappaB-mediated cytoprotective effects in human non-small cell lung cancer cells. Mol Cancer Ther 5(2):391–399PubMedCrossRefGoogle Scholar
  214. 214.
    Sreenivasan Y, Sarkar A, Manna SK (2003) Oleandrin suppresses activation of nuclear transcription factor-kappa B and activator protein-1 and potentiates apoptosis induced by ceramide. Biochem Pharmacol 66(11):2223–2239PubMedCrossRefGoogle Scholar
  215. 215.
    Aggarwal BB, Shishodia S (2004) Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning. Ann N Y Acad Sci 1030:434–441PubMedCrossRefGoogle Scholar
  216. 216.
    Bachmeier BE, Mohrenz IV, Mirisola V, Schleicher E, Romeo F, Hohneke C et al (2008) Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB. Carcinogenesis 29(4):779–789PubMedCrossRefGoogle Scholar
  217. 217.
    Ravindran J, Prasad S, Aggarwal BB (2009) Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? AAPS J 11(3):495–510PubMedCrossRefGoogle Scholar
  218. 218.
    Alexandrow MG, Song LJ, Altiok S, Gray J, Haura EB, Kumar NB (2012) Curcumin: a novel Stat3 pathway inhibitor for chemoprevention of lung cancer. Eur J Cancer Prev 21(5):407–412PubMedCrossRefGoogle Scholar
  219. 219.
    Jeong WS, Kim IW, Hu R, Kong AN (2004) Modulation of AP-1 by natural chemopreventive compounds in human colon HT-29 cancer cell line. Pharm Res 21(4):649–660PubMedCrossRefGoogle Scholar
  220. 220.
    Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J et al (2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61(7):3071–3076PubMedGoogle Scholar
  221. 221.
    Tummala R, Romano RA, Fuchs E, Sinha S (2003) Molecular cloning and characterization of AP-2 epsilon, a fifth member of the AP-2 family. Gene 321:93–102PubMedCrossRefGoogle Scholar
  222. 222.
    Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D et al (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101(6):2377–2380PubMedCrossRefGoogle Scholar
  223. 223.
    Nencioni A, Wille L, Dal Bello G, Boy D, Cirmena G, Wesselborg S et al (2005) Cooperative cytotoxicity of proteasome inhibitors and tumor necrosis factor-related apoptosis-inducing ligand in chemoresistant Bcl-2-overexpressing cells. Clin Cancer Res 11(11):4259–4265PubMedCrossRefGoogle Scholar
  224. 224.
    Yanamandra N, Colaco NM, Parquet NA, Buzzeo RW, Boulware D, Wright G et al (2006) Tipifarnib and bortezomib are synergistic and overcome cell adhesion-mediated drug resistance in multiple myeloma and acute myeloid leukemia. Clin Cancer Res 12(2):591–599PubMedCrossRefGoogle Scholar
  225. 225.
    Burke JR, Pattoli MA, Gregor KR, Brassil PJ, MacMaster JF, McIntyre KW et al (2003) BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice. J Biol Chem 278(3):1450–1456PubMedCrossRefGoogle Scholar
  226. 226.
    Olivier S, Robe P, Bours V (2006) Can NF-kappaB be a target for novel and efficient anti-cancer agents? Biochem Pharmacol 72(9):1054–1068PubMedCrossRefGoogle Scholar
  227. 227.
    Shao L, Wu L, Zhou D (2012) Sensitization of tumor cells to cancer therapy by molecularly targeted inhibition of the inhibitor of nuclear factor kappaB kinase. Transl Cancer Res 1(2):100–108PubMedGoogle Scholar
  228. 228.
    Xia Y, Choi HK, Lee K (2012) Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors. Eur J Med Chem 49:24–40PubMedCrossRefGoogle Scholar
  229. 229.
    Horiguchi A, Asano T, Kuroda K, Sato A, Asakuma J, Ito K et al (2010) STAT3 inhibitor WP1066 as a novel therapeutic agent for renal cell carcinoma. Br J Cancer 102(11): 1592–1599PubMedCrossRefGoogle Scholar
  230. 230.
    Zhang X, Yue P, Page BD, Li T, Zhao W, Namanja AT et al (2012) Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts. Proc Natl Acad Sci USA 109(24):9623–9628PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Kunzang Chosdol
    • 1
  • Mohita Bhagat
    • 1
  • Bhawana Dikshit
    • 1
  • Evanka Madan
    • 1
  • Parthaprasad Chattopadhyay
    • 1
  • Subrata Sinha
    • 2
  1. 1.Department of BiochemistryAll India Institute of Medical SciencesNew DelhiIndia
  2. 2.National Brain Research Centre (NBRC)ManesarIndia

Personalised recommendations