Advertisement

NF-κB, IκB Kinase and Interacting Signal Networks in Squamous Cell Carcinomas

  • Antonio Costanzo
  • Giulia Spallone
  • Michael KarinEmail author
Chapter

Abstract

Nuclear factor-κB (NF-κB) transcription factors and the IκB kinases (IKKs) that activate them are central coordinators of innate and adaptive immune responses. More recently, it has become clear that NF-κB signaling also has a critical role in cancer development and progression. The canonical NF-κB pathway contributes to squamous cell carcinoma (SCC) development by interacting with other signaling pathways including tumor suppressive and oncogenic pathways in a tissue specific manner. In this chapter, we will summarize recent advances in the understanding of interconnections between NF-κB and IKKs, including IKKα which has NF-κB independent functions, in the context of SCC development and progression and as potential target for novel chemotherapy approaches.

Keywords

Squamous Cell Carcinoma Squamous Cell Carcinoma Cell Line Human Squamous Cell Carcinoma HNSCC Cell RelA Phosphorylation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Adams J, Palombella VJ, Sausville EA et al. (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59:2615–2622PubMedGoogle Scholar
  2. Alam M, Ratner D (2001) Cutaneous squamous-cell carcinoma. N Engl J Med 344:975–983PubMedCrossRefGoogle Scholar
  3. Amornphimoltham P, Sriuranpong V, Patel V et al. (2004) Persistent activation of the Akt pathway in head and neck squamous cell carcinoma: a potential target for UCN-01. Clin Cancer Res 10:4029–4037PubMedCrossRefGoogle Scholar
  4. Angel P, Szabowski A, Schorpp-Kistner M (2001) Function and regulation of AP-1 subunits in skin physiology and pathology. Oncogene 20:2413–2423PubMedCrossRefGoogle Scholar
  5. Arnott CH, Scott KA, Moore RJ, Robinson SC, Thompson RG, Balkwill FR (2004) Expression of both TNF-a receptor subtypes is essential for optimal skin tumour development. Oncogene 23:1902–1910PubMedCrossRefGoogle Scholar
  6. Balkwill F (2002) Tumor necrosis factor or tumor promoting factor? Cytokine Growth Factor Rev 13:135–141PubMedCrossRefGoogle Scholar
  7. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545PubMedCrossRefGoogle Scholar
  8. Baud V, Karin M (2001) Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 11:372PubMedCrossRefGoogle Scholar
  9. Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D (July 13, 1995) Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 376(6536):167–170PubMedCrossRefGoogle Scholar
  10. Bender K, Gottlicher M, Whiteside S, Rahmsdorf HJ, Herrlich P (1998) Sequential DNA damage-independent and-dependent activation of NF-κB by UV. EMBO J 17:5170–5181PubMedCrossRefGoogle Scholar
  11. Beraud C, Henzel WJ, Baeuerle PA (1999) Involvement of regulatory and catalytic subunits of phosphoinositide 3-kinase in NF-κB activation. Proc Natl Acad Sci USA 96:429–434PubMedCrossRefGoogle Scholar
  12. Bonizzi G, Karin M (2004) The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25:280–288PubMedCrossRefGoogle Scholar
  13. Chang AA, Chen Z, Ricker JL et al. (2004) Induction of apoptosis and regulation of inhibitor of apoptosis-1 protein and cyclin D1 expression in head and neck cancer cell lines by PS 241/bortezomib (VELCADE)., a novel proteasome inhibitor. Proc Am Assoc Cancer Res 95:4007Google Scholar
  14. Chen G, Goeddel DV (2002) TNF-R1 signaling: a beautiful pathway. Science. 296(5573):1634–1635.PubMedCrossRefGoogle Scholar
  15. Chen JG, Fleischer AB, Smith ED et al. (2001a) Cost of non melanoma skin cancer treatment in the United States. Dermatol Surg 27:1035–1038PubMedCrossRefGoogle Scholar
  16. Chen N, Nomura M, She QB et al. (2001b) Suppression of skin tumorigenesis in c-Jun ­NH­(2)-terminal kinase-2-deficient mice. Cancer Res 61:3908–3912PubMedGoogle Scholar
  17. Chen Z, Ricker JL, Malhotra PS, Nottingham L, Bagain L, Lee TL, Yeh NT, Van Waes C (2008) Differential bortezomib sensitivity in head and neck cancer lines corresponds to proteasome, nuclear factor-kappaB and activator protein-1 related mechanisms. Mol Cancer Ther 7(7):1949–60PubMedCrossRefGoogle Scholar
  18. Cohen J et al. (2009) Attenuated transforming growth factor beta signaling promotes nuclear ­factor-kappaB activation in head and neck cancer. Cancer Res 69(8):3415–3424PubMedCrossRefGoogle Scholar
  19. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867PubMedCrossRefGoogle Scholar
  20. Dajee M, Larzarov M, Zhang JY et al. (2003) NF-κB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421:639–643PubMedCrossRefGoogle Scholar
  21. Dassonville O, Formento JL, Francoual M, Ramaioli A, Santini J, Schneider M, Demard F, Milano G (1993) Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J Clin Oncol 11:1873–1878PubMedGoogle Scholar
  22. Derynck R, Akhurst RJ, Balmain A (2001) TGF-b signaling in tumor suppression and cancer progression. Nat Genet 29:117–129PubMedCrossRefGoogle Scholar
  23. Descargues P, Sil AK, Sano Y, Korchynskyi O, Han G, Owens P, Wang XJ, Karin M (2008) IKKalpha is a critical coregulator of a Smad4-independent TGFbeta-Smad2/3 signaling pathway that controls keratinocyte differentiation. Proc Natl Acad Sci USA 105(7):2487–2492PubMedCrossRefGoogle Scholar
  24. Deyoung MP, Ellisen LW (2007) p63 and p73 in human cancer: defining the network. Oncogene 26(36):5169–5183PubMedCrossRefGoogle Scholar
  25. Druker BJ, Neumann M, Okuda K, RJ FB, Griffin JD (1994) rel Is rapidly tyrosine-phosphorylated following granulocyte-colony stimulating factor treatment of human neutrophils. J Biol Chem 269:5387–5390PubMedGoogle Scholar
  26. Duffey DC, Chen Z, Dong G, Ondrey FG, Wolf JS, Brown K, Siebenlist U, Van Waes C (1999) Expression of a dominant-negative mutant inhibitor-kappaBalpha of nuclear factor-kappaB in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo. Cancer Res 59(14):3468–3474PubMedGoogle Scholar
  27. Duffey DC, Crowl-Bancroft CV, Chen Z, Ondrey FG, Nejad-Sattari M, Dong G, Van Waes C (2000) Inhibition of transcription factor nuclear factor-kappaB by a mutant inhibitor-kappaBalpha attenuates resistance of human head and neck squamous cell carcinoma to TNF-alpha caspase-mediated cell death. Br J Cancer 83(10):1367–1374PubMedCrossRefGoogle Scholar
  28. El-Omar EM et al. (2000) Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404:398–402PubMedCrossRefGoogle Scholar
  29. Fognani C, Rondi R, Romano A, Blasi F (2000) cRel-TD kinase: a serine/threonine kinase binding in vivo and in vitro c-Rel and phosphorylating its transactivation domain. Oncogene 19:2224–2232PubMedCrossRefGoogle Scholar
  30. Forastiere A, Koch W, Trotti A, Sidransky D (2001) Head and neck cancer. N Engl J Med 345:1890–1900PubMedCrossRefGoogle Scholar
  31. Gasparian AV, Guryanova OA, Chebotaev DV, Shishkin AA, Yemelyanov AY, Budunova IV (2009) Targeting transcription factor NF-κB: comparative analysis of proteasome and IKK inhibitors. Cell Cycle 8(10):1559–1566PubMedCrossRefGoogle Scholar
  32. Gerondakis S, Grumont R, Gugasyan R, Wong L, Isomura I, Ho W, Banerjee A (2006) Unravelling the complexities of the NF-kappaB signalling pathway using mouse knockout and transgenic models. Oncogene 25(51):6781–6799PubMedCrossRefGoogle Scholar
  33. Gomis RR et al. (2006a) A FoxO-Smad synexpression group in human keratinocytes. Proc Natl Acad Sci U S A 103:12747–12752PubMedCrossRefGoogle Scholar
  34. Gomis RR et al. (2006b) C/EBPb at the core of the TGF_ cytostatic response and its evasion in metastatic breast cancer cells. Cancer Cell 10:203–214PubMedCrossRefGoogle Scholar
  35. Grandis JR, Tweardy DJ (1993) Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 53:3579–3584PubMedGoogle Scholar
  36. Grandis J, Melhem MF, Gooding WE, Day R, Holst VA, Wagener MM, Drenning SD, Tweardy DJ (1998a) Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 90:824–832CrossRefGoogle Scholar
  37. Grandis JR, Drenning SD, Chakraborty A, Zhou MY, Zeng Q, Pitt AS, Tweardy DJ (1998b) Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor-mediated cell growth in vitro. J Clin Invest 102:1385–1392PubMedCrossRefGoogle Scholar
  38. Grandis J, Zeng Q, Drenning SD (2000) Epidermal growth factor receptor-mediated stat3 signaling blocks apoptosis in head and neck cancer. Laryngoscope 110:868–874CrossRefGoogle Scholar
  39. Grivennikov S, Karin E, Terzic J et al. (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15(2):103–113PubMedCrossRefGoogle Scholar
  40. Guan H, Hou S, Ricciardi RP (2005) DNA binding ofrepressor NF-κB p50/p50 depends on phosphorylation of Ser337 by the protein kinase A catalytic subunit. J Biol Chem 280:9957–9962PubMedCrossRefGoogle Scholar
  41. Gulati AP, Yang YM, Harter D et al. (2006) Mutant human tumor suppressor p53 modulates the activation of mitogen-activated protein kinase and nuclear factorkB, but not c-Jun N-terminal kinase and activated protein-1. Mol Carcinog 45:26–37PubMedCrossRefGoogle Scholar
  42. Häcker H, Karin M (2006) Regulation and function of IKK and IKK-related kinases. Sci STKE 357:re13CrossRefGoogle Scholar
  43. Haider AS, Duculan J, Whynot JA, Krueger JG (2006) Increased JunB mRNA and protein expression in psoriasis vulgaris lesions. J Invest Dermatol 126:912914Google Scholar
  44. Han G et al (2005) Distinct mechanisms of TGF_1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis. J Clin Invest 115:1714–1723PubMedCrossRefGoogle Scholar
  45. Hayden MS, Ghosh S (2004) Signaling to NF-κB. Genes Dev 18:2195–2224PubMedCrossRefGoogle Scholar
  46. Hinata K, Gervin AM, Jennifer Zhang Y, Khavari PA (2003) Divergent gene regulation and growth effects by NF-kappa B in epithelial and mesenchymal cells of human skin. Oncogene 22(13):1955–1964PubMedCrossRefGoogle Scholar
  47. Hoberg JE, Popko AE, Ramsey CS, Mayo MW (2006) IKKα-mediated derepression of SMRT potentiates acetylation of RelA/p65 by p300. Mol Cell Biol 26:457–471PubMedCrossRefGoogle Scholar
  48. Hong et al (2007) Smad7 binds to the adaptors TAB2 and TAB3 to block recruitment of the kinase TAK1 to the adaptor TRAF2. Nat Immunol 8(5):504–513CrossRefGoogle Scholar
  49. Hong SH, Ondrey FG, Avis IM, Chen Z, Loukinova E, Cavanaugh PF Jr, Van Waes C, Mulshine JL (2000) Cyclooxygenase regulates human oropharyngeal carcinomas via the proinflammatory cytokine IL-6: a general role for inflammation? FASEB J 14(11):1499–1507PubMedCrossRefGoogle Scholar
  50. Hu Y, Baud V, Oga T, Kim KI, Yoshida K, Karin M (2001) IKKalpha controls formation of the epidermis independently of NF-kappaB. Nature 410(6829):710–714PubMedCrossRefGoogle Scholar
  51. Huntley SP, Davies M, Matthews JB et al (2004) Attenuated type II TGF-h receptor signalling in human malignant oral keratinocytes induces a less differentiated and more aggressive phenotype that is associated with metastatic dissemination. Int J Cancer 110:170–176PubMedCrossRefGoogle Scholar
  52. Imbert V, Rupec RA, Livolsi A et al. (1996) Tyrosine phosphorylation of IκBa activates NF-κBwithout proteolytic degradation of IκBa. Cell 86:787–798PubMedCrossRefGoogle Scholar
  53. Jackson-Bernitsas DG, Ichikawa H, Takada Y, Myers JN, Lin XL, Darnay BG, Chaturvedi MM, Aggarwal BB (2007) Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-kappaB activation and proliferation in human head and neck squamous cell carcinoma. Oncogene 26(10):1385–97PubMedCrossRefGoogle Scholar
  54. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics. CA Cancer J Clin 59(4):225–249PubMedCrossRefGoogle Scholar
  55. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M (2005) Reactive oxygen species promote TNF-alpha-induced death and sustained JNK activation by inhibiting MAPkinase phosphatases. Cell 120(5):649–661PubMedCrossRefGoogle Scholar
  56. Kandel ES (2009) NF-kappaB inhibition and more: A side-by-side comparison of the inhibitors of IKK and proteasome. Cell Cycle 8(12):1819–1820PubMedCrossRefGoogle Scholar
  57. Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441(7092):431–436PubMedCrossRefGoogle Scholar
  58. Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 18:621–663PubMedCrossRefGoogle Scholar
  59. Karin M, Cao Y, Greten FR, Li ZW (2002) NF-κB in Cancer: From innocent bystander to major culprit. Nat Rev Cancer 2(4):301–310PubMedCrossRefGoogle Scholar
  60. Karin M, Lawrence T, Nizet V (2006) Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124(4):823–835PubMedCrossRefGoogle Scholar
  61. Kato T Jr, Delhase M, Hoffmann A, Karin M (2003) CK2 Is a C-Terminal IkappaB Kinase Responsible for NF-kappaB Activation during the UV Response. Mol Cell 4:829–839CrossRefGoogle Scholar
  62. King et al. (2008) The p53 homologue DeltaNp63alpha interacts with the nuclear factor-kappaB pathway to modulate epithelial cell growth. Cancer Res 68(13):5122–5131CrossRefGoogle Scholar
  63. Kong A, Leboucher P, Leek R, Calleja V, Winter S, Harris A, Parker PJ, Larijani B (2006) Prognostic value of an activation state marker for epidermal growth factor receptor in tissue microarrays of head and neck cancer. Cancer Res 66:2834–2843PubMedCrossRefGoogle Scholar
  64. Kuper H, Adami HO, Trichopoulos D (2000) Infections as a major preventable cause of human cancer. J Intern Med 248(3):171–183PubMedCrossRefGoogle Scholar
  65. Lawrence T, Bebien M, Liu GY, Nizet V, Karin M (2005) IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation. Nature 434:1138–1143PubMedCrossRefGoogle Scholar
  66. Lazarov M, Kobo Y, Cai T et al. (2002) CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis. Nat Med 8:1105–1114PubMedCrossRefGoogle Scholar
  67. Lee DF, Hung MC (2008) Advances in targeting IKKα and IKK-related kinases for cancer therapy. Clin Cancer Res 14(18):5656–5662PubMedCrossRefGoogle Scholar
  68. Lee TL, Yeh J, Van Waes C, Chen Z (2006) Epigenetic modification of SOCS-1 differentially regulates STAT3 activation in response to interleukin-6 receptor and epidermal growth factor receptor signaling through JAK and/or MEK in head and neck squamous cell carcinomas. Mol Cancer Ther 5(1):8–19PubMedCrossRefGoogle Scholar
  69. Lee TL, Yeh J, Friedman J, Yan B, Yang X, Yeh NT, Van Waes C, Chen Z (2008) A signal network involving coactivated NF-kappaB and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas. Int J Cancer 122(9):1987–1998PubMedCrossRefGoogle Scholar
  70. Levrero M, De Laurenzi V, Costanzo A, Gong J, Wang JY, Melino G (2000) The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J Cell Sci 113(Pt 10):1661–1670PubMedGoogle Scholar
  71. Li N, Karin M (1998) Ionizing radiationand short wavelength UV activate NF-κB through two distinct mechanisms. Proc Natl Acad Sci U S A 95:13012–13017PubMedCrossRefGoogle Scholar
  72. Li AG, Lu SL, Han G, Hoot KE, Wang XJ (2006) Role of TGFβ in skin inflammation and carcinogenesis. Mol Carcinog 45:389–396PubMedCrossRefGoogle Scholar
  73. Lind MH, Rozell B, Wallin RP, van Hogerlinden M, Ljunggren HG, Toftgard R, Sur I (2004) Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-kappaB inhibition. Proc Natl Acad Sci USA 10:4972–4977CrossRefGoogle Scholar
  74. Liu Y, Denlinger CE, Rundall BK, Smith PW, Jones DR (2006) Suberoylanilide hydroxamic acid induces Aktmediated phosphorylation of p300, which promotes acetylation and transcriptional activation of RelA/p65. J Biol Chem 281:31359–31368PubMedCrossRefGoogle Scholar
  75. Lizzul PF, Aphale A, Malaviya R, Sun Y, Masud S, Dombrovskiy V, Gottlieb AB (2005) Differential expression of phosphorylated NF-kappaB/RelA in normal and psoriatic epidermis and downregulation of NF-kappaB in response to treatment with etanercept. J Invest Dermatol 124(6):1275–1283PubMedCrossRefGoogle Scholar
  76. Lu SL et al. (2006) Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev 20(10):1331–1342PubMedCrossRefGoogle Scholar
  77. Maeda G, Chiba T, Kawashiri S, Satoh T, Imai K (2007) Epigenetic inactivation of IkappaB Kinase-alpha in oral carcinomas and tumor progression. Clin Cancer Res 13:5041–5047PubMedCrossRefGoogle Scholar
  78. Marienfeld R, Berberich-Siebelt F, Berberich I, Denk A, Serfling E, Neumann M (2001) Signal-specific and phosphorylation-dependent RelB degradation: a potential mechanism of NF-κB control. Oncogene 20:8142–8147PubMedCrossRefGoogle Scholar
  79. Marinari B, Moretti F, Botti E et al. (2008) he tumor suppressor activity of IKKalpha in stratified epithelium is exerted in part via the TGF-beta anti proliferative pathway. Proc Natl Acad Sci USA 105(44):17091–17096PubMedCrossRefGoogle Scholar
  80. Markowitz SD, Roberts AB (1996) Tumor suppressor activity ofthe TGFβ pathway in human cancers. Cytokine Growth Factor Rev 7:93–102PubMedCrossRefGoogle Scholar
  81. Mehic D, Bakiri L, Ghannadan M, Wagner EF, Tschachler E (2005) Fos and jun proteins are specifically expressed during differentiation of human keratinocytes. J Invest Dermatol 124:212–220PubMedCrossRefGoogle Scholar
  82. Miller DL, Weinstock MA (1994) Nonmelanoma skin cancer in the United States: incidence. J Am Acad Dermatol 30:774–778PubMedCrossRefGoogle Scholar
  83. Miyamoto S, Verma IM (1995) RE1/NF-κB/IκB story. Adv Cancer Res 66:255–292PubMedCrossRefGoogle Scholar
  84. Murray AW (2004) Recycling the cell cycle: cyclins revisited. Cell 116(2):221–234. Review PubMed PMID: 1474433PubMedCrossRefGoogle Scholar
  85. Naugler WE, Karin M (2008) NF-κB and cancer – identifying targets and mechanisms. Curr Opin Genet Dev 18(1):19–26PubMedCrossRefGoogle Scholar
  86. Naumann M, Scheidereit C (1994) Activation of NF-κB in vivo is regulated by multiple phosphorylations. EMBO J 13:4597–4607PubMedGoogle Scholar
  87. Nelson DE, Ihekwaba AE, Elliot M et al. (2004) Oscillations in NF-κB signaling control the dynamics of gene expression. Science 306:704–708PubMedCrossRefGoogle Scholar
  88. Nickoloff BJ (2001) Creation of psoriatic plaques: the ultimate tumor suppressor pathway. A new model for an ancient T-cell-mediated skin disease. J Cutan Pathol 28(2):57–64, ReviewPubMedCrossRefGoogle Scholar
  89. Nishimoto N, Kishimoto T, Yoshizaki K (2000) Anti-interleukin 6 receptor antibody treatment in rheumatic disease. Ann Rheum Dis 59(Suppl 1):i21–127PubMedCrossRefGoogle Scholar
  90. Oft M et al (1996) TGFα1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 10:2462–2477PubMedCrossRefGoogle Scholar
  91. Oft M, Heider KH, Beug H (1998) TGFβ signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 8:1243–1252PubMedCrossRefGoogle Scholar
  92. Ondrey FG, Dong G, Sunwoo J, Chen Z, Wolf JS, Crowl-Bancroft CV, Mukaida N, Van Waes C (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 26:119–129PubMedCrossRefGoogle Scholar
  93. Parkin DM, Bray F, Ferlay J, Pisani P (2001) Estimating the world cancer burden: Globocan. Int J Cancer 94(2):153–156PubMedCrossRefGoogle Scholar
  94. Pazzaglia S et al (2001) Analysis of c-Ha-ras gene mutations in skin tumors induced in carcinogenesis susceptible and carcinogenesis-resistant mice by different two-stage protocols or tumour promoter alone. Mol Carcinog 30:111–118PubMedCrossRefGoogle Scholar
  95. Perkins ND (2006) Post-translational modifications regulating the activity and function of the NF-κB pathway. Oncogene 25:6717–6730PubMedCrossRefGoogle Scholar
  96. Roder DM (2002) The epidemiology of gastric cancer. Gastric Cancer 5(Suppl 1):5–11PubMedCrossRefGoogle Scholar
  97. Roman-Blas JA, Jimenez SA (2008) Targeting NF-kappaB: a promising molecular therapy in inflammatory arthritis. Int Rev Immunol 27(5):351–374PubMedCrossRefGoogle Scholar
  98. Sabapathy K, Hochedlinger K, Nam SY, Bauer A, Karin M, Wagner EF (2004) Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Mol Cell 15:713–725PubMedCrossRefGoogle Scholar
  99. Saunders G (2005) Overview of drug therapy for multiple myeloma. J Oncol Pharm Pract 11:83–100PubMedCrossRefGoogle Scholar
  100. Scian MJ, Stagliano KE, Anderson MA et al. (2005) Tumor derived p53 mutants induce NF-κB2 gene expression. Mol Cell Biol 25:10097–10110PubMedCrossRefGoogle Scholar
  101. Sebens S, Arlt A, Schäfer H (2008) NF-kappaB as a molecular target in the therapy of pancreatic carcinoma. Recent Results Cancer Res 177:151–164PubMedCrossRefGoogle Scholar
  102. Seitz CS, Lin Q, Deng H, Khavari PA (1998) Alterations in NF-kB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-kB. Proc Natl Acad Sci USA 95(2307–2312):2340Google Scholar
  103. Sen R, Baltimore D (1986) Inducibility of the immunoglobulin enhancer-binding protein NF-κB by a posttranslational mechanism. Cell 47:921–928PubMedCrossRefGoogle Scholar
  104. She QB, Chen N, Bode AM, Flavell RA, Dong Z (2002) Deficiency of c-Jun-NH2-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 62:1343–1348PubMedGoogle Scholar
  105. Siegel PM, Massague J (2003) Cytostatic and apoptotic actions of TGFβ in homeostasis and cancer. Nat Rev Cancer 3:807–821PubMedCrossRefGoogle Scholar
  106. Squarize CH, Castilho RM, Sriuranpong V, Pinto DS Jr, Gutkind JS (2006) Molecularcross-talk between the NF-kappaB and STAT3 signaling pathways in head and necksquamous cell carcinoma. Neoplasia 9:733–746CrossRefGoogle Scholar
  107. Sriuranpong V, Park JI, Amornphimoltham P, Patel V, Nelkin BD, Gutkind JS (2003) Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. Cancer Res 63:2948–2956PubMedGoogle Scholar
  108. Strano S, Dell’Orso S, Di Agostino S, Fontemaggi G, Sacchi A, Blandino G (2007) Mutant p53: an oncogenic transcription factor. Oncogene 26(15):2212–2219, ReviewPubMedCrossRefGoogle Scholar
  109. Sun J et al. (2005) Sequence variants in Toll-like receptorgene cluster (TLR6–TLR1–TLR10). and prostate cancer risk. J Natl Cancer Inst 97:525–532PubMedCrossRefGoogle Scholar
  110. Sunwoo JB, Chen Z, Dong G, Yeh N, Crowl Bancroft C, Sausville E, Adams J, Elliott P, Van Waes C (2001) Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res 7(5):1419–1428PubMedGoogle Scholar
  111. Szczepanski MJ et al. (2009) Triggering of Toll-like receptor 4 expressed on human head and neck squamous cell carcinoma promotes tumor development and protects the tumor from immune attack. Cancer Res 69(7):3105–3113PubMedCrossRefGoogle Scholar
  112. Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J (1999) The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res 5:2638–2645PubMedGoogle Scholar
  113. van Hogerlinden M, Rozell BL, Ahrlund-Richter L, Toftgard R (1999) Squamous cell carcinomas and increased apoptosis in skin with inhibited Rel/nuclear factor-kB signaling. Cancer Res 59:3299–3303PubMedGoogle Scholar
  114. Van Waes C (2007) Nuclear factor-kappaB in development, prevention, and therapy of cancer. Clin Cancer Res 13(4):1076–1082PubMedCrossRefGoogle Scholar
  115. Van Waes C, Sunwoo JB, DeGraff W et al. (2004) Radiosensitization and proteasome inhibition. In: Adams J (ed) Cancer drug discovery and development: proteasome inhibitors in cancer therapy. Humana, Totowa, pp 123–131Google Scholar
  116. Van Waes C et al. (2005) Inhibition of nuclear factor-kappaB and target genes during combined therapy with proteasome inhibitor bortezomib and reirradiation in patients with recurrent head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 63(5):1400–1412PubMedCrossRefGoogle Scholar
  117. Viatour P, Merville M-P, Bours V, Chariot A (2005) Phosphorylation of NF-κB and IκB proteins: implications in cancer and inflammation. Trends Biochem Sci 30:43–52PubMedCrossRefGoogle Scholar
  118. Wang D, Song H, Evans JA, Lang JC, Schuller DE, Weghorst CM (1997) Mutation and down-regulation ofthe transforming growth factor h type II receptor gene in primary squamous cell carcinomas ofthe head and neck. Carcinogenesis 18:2285–2290PubMedCrossRefGoogle Scholar
  119. Wang WH et al. (2003) Non-steroidal anti-inflammatory drug use and the risk of gastric cancer: a systematic review and meta-analysis. J Natl Cancer Inst 95:1784–1791PubMedGoogle Scholar
  120. Warzocha K et al. (1998) Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin’s lymphoma outcome. Blood 91:3574–3581PubMedGoogle Scholar
  121. Weisz L, Oren M, Rotter V (2007a) Transcription regulation by mutant p53. Oncogene 26(15):2202–2211, ReviewPubMedCrossRefGoogle Scholar
  122. Weisz L, Damalas A, Liontos M et al. (2007b) Mutant p53 enhances nuclear factor kappaB activation by tumor necrosis factor alpha in cancer cells. Cancer Res 67(6):2396–2401PubMedCrossRefGoogle Scholar
  123. Wolf JS 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
  124. Wu MH, Chen XY, Cai KR (2009) Effects of a JAK inhibitor, AG490, on proliferation and apoptosis of human nasopharyngeal carcinoma cell line CNE-2Z. Ai Zheng 28(1):24–28PubMedGoogle Scholar
  125. Xu Y, Davidson L, Alt FW, Baltimore D (1996) Deletion of the Ig kappa light chainintronic enhancer/matrix attachment region impairs but does not abolish V kappa J kappa rearrangement. Immunity 4:377–385PubMedCrossRefGoogle Scholar
  126. Yamamoto Y, Gaynor RB (2001) Therapeutic potential of inhibition of the NF-kB pathway in the treatment of inflammation and cancer. J Clin Invest 107:135–142PubMedCrossRefGoogle Scholar
  127. Yuspa SH (1994) The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis. The thirty-third G. H. A. Clowes Memorial Award Lecture. Cancer Res 54:1178–1189PubMedGoogle Scholar
  128. Zhang JY, Adams AE, Ridky TW, Tao S, Khavari PA (2007) Tumor necrosis factor receptor 1/c-Jun-NH2-kinase signaling promotes human neoplasia. Cancer Res 67(8):3827–3834PubMedCrossRefGoogle Scholar
  129. Zhong H, May MJ, Jimi E, Ghosh S (2002) The phosphorylation status of nuclear NF-κB determines its association with CBP/p300 or HDAC-1. Mol Cell 9:625–636PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Antonio Costanzo
  • Giulia Spallone
  • Michael Karin
    • 1
    Email author
  1. 1.Laboratory of Gene Regulation and Signal Transduction, School of MedicineUniversity of California, San DiegoLa JollaUSA

Personalised recommendations