NF-κB Role and Potential Drug Targets in Gastrointestinal Cancer

  • Prudhvi Lal Bhukya
  • Rongala Laxmivandana
  • Gopinath Meenakshi Sundaram
Chapter

Abstract

A multifactorial disease cancer arises due to mutation in the gene encoding particular transcription factor or proteins. Globally cancer is one of the diseases which is responsible for maximum mortality annually. Transcription factor plays an important role in cell physiology, and any alteration in this transcription factor may lead to diseases like cancers. NF-κB is a transcription factor which has immense homeostasis role in cell physiology and in several diseases. NF-κB is actively expressed in many cancers and helps in initiations, cell proliferations, and metastasis of different cancers. The present chapter discusses the role of NF-κB in cancer promotion and different drug targets, targeting NF-κB pathway for the treatment of cancers.

Keywords

NF-κB Carcinogenesis Treatment Noncanonical pathway and canonical pathways 

References

  1. 1.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70PubMedCrossRefGoogle Scholar
  2. 2.
    Gilmore TD, Temin HM (1986) Different localization of the product of the v-rel oncogene in chicken fibroblasts and spleen cells correlates with transformation by REV-T. Cell 44(5):791–800PubMedCrossRefGoogle Scholar
  3. 3.
    Sen R, Baltimore D (1986) Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46(5):705–716PubMedCrossRefGoogle Scholar
  4. 4.
    Baeuerle PA, Baltimore D (1988) IKB: a specific inhibitor of the NF-κ ‘B transcription factor. Science 242:540–546Google Scholar
  5. 5.
    Stephens RM, Rice NR, Hiebsch RR, Bose HR, Gilden RV (1983) Nucleotide sequence of v-rel: the oncogene of reticuloendotheliosis virus. Proc Natl Acad Sci 80(20):6229–6233PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Urban MB, Baeuerle PA (1991) The role of the p50 and p65 subunits of NF-kappa B in the recognition of cognate sequences. New Biol 3(3):279–288PubMedGoogle Scholar
  7. 7.
    Devin A, Cook A, Lin Y, Rodriguez Y, Kelliher M, Liu ZG (2000) The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation. Immunity 12(4):419–429PubMedCrossRefGoogle Scholar
  8. 8.
    Hatada EN, Nieters A, Wulczyn FG, Naumann M, Meyer R, Nucifora G, …, Scheidereit C (1992) The ankyrin repeat domains of the NF-kappa B precursor p105 and the protooncogene bcl-3 act as specific inhibitors of NF-kappa B DNA binding. Proc Natl Acad Sci 89(6):2489–2493Google Scholar
  9. 9.
    Rothwarf DM, Karin M (1999) The NF-κB activation pathway: a paradigm in information transfer from membrane to nucleus. Sci STKE 1999(5), re1Google Scholar
  10. 10.
    Ghosh, S., Karin, M. (2002). Missing pieces in the NF-κB puzzle. Cell, 109(2):S81–S96Google Scholar
  11. 11.
    Ghosh S, May MJ, Kopp EB (1998a) NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16(1):225–260PubMedCrossRefGoogle Scholar
  12. 12.
    Sun SC, Ley SC (2008) New insights into NF-κB regulation and function. Trends Immunol 29(10):469–478PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol 18(1):621–663PubMedCrossRefGoogle Scholar
  14. 14.
    Kato T, Delhase M, Hoffmann A, Karin M (2003) CK2 is a C-terminal IκB kinase responsible for NF-κB activation during the UV response. Mol Cell 12(4):829–839PubMedCrossRefGoogle Scholar
  15. 15.
    Tergaonkar V, Bottero V, Ikawa M, Li Q, Verma IM (2003) IκB kinase-independent IκBα degradation pathway: functional NF-κB activity and implications for cancer therapy. Mol Cell Biol 23(22):8070–8083PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Silverman N, Maniatis T (2001) NF-κB signaling pathways in mammalian and insect innate immunity. Genes Dev 15(18):2321–2342PubMedCrossRefGoogle Scholar
  17. 17.
    Bonizzi G, Karin M (2004) The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25(6):280–288PubMedCrossRefGoogle Scholar
  18. 18.
    Aggarwal BB (2004a) Nuclear factor-κB: the enemy within. Cancer Cell 6(3):203–208PubMedCrossRefGoogle Scholar
  19. 19.
    Chen ZJ (2005a) Ubiquitin signalling in the NF-κB pathway. Nat Cell Biol 7(8):758–765PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Barkett M, Gilmore TD (1999) Control of apoptosis by Rel/NF-κB transcription factors. Oncogene 18(49):6910PubMedCrossRefGoogle Scholar
  21. 21.
    Marusawa H, Hijikata M, Chiba T, Shimotohno K (1999) Hepatitis C virus core protein inhibits Fas-and tumor necrosis factor alpha-mediated apoptosis via NF-κB activation. J Virol 73(6):4713–4720PubMedPubMedCentralGoogle Scholar
  22. 22.
    Singh N, Kumar S, Singh P, Raj HG, Prasad AK, Parmar VS, Ghosh B (2008) Piper longum Linn. Extract inhibits TNF-α-induced expression of cell adhesion molecules by inhibiting NF-κB activation and microsomal lipid peroxidation. Phytomedicine 15(4):284–291PubMedCrossRefGoogle Scholar
  23. 23.
    Shou Y, Li N, Li L, Borowitz JL, Isom GE (2002) NF-κB-mediated up-regulation of Bcl-XS and Bax contributes to cytochrome c release in cyanide-induced apoptosis. J Neurochem 81(4):842–852PubMedCrossRefGoogle Scholar
  24. 24.
    Karin M, Greten FR (2005) NF-κB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5(10):749–759PubMedCrossRefGoogle Scholar
  25. 25.
    Pahl HL (1999) Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18(49):6853PubMedCrossRefGoogle Scholar
  26. 26.
    Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Kuramoto A (1988) Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332:83PubMedCrossRefGoogle Scholar
  27. 27.
    Osborn L, Hession C, Tizard R, Vassallo C, Luhowskyj S, Chi-Rosso G, Lobb R (1989) Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell 59(6):1203–1211PubMedCrossRefGoogle Scholar
  28. 28.
    Biswas DK, Cruz AP, Gansberger E, Pardee AB (2000) Epidermal growth factor-induced nuclear factor κB activation: a major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells. Proc Natl Acad Sci 97(15):8542–8547PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Myers RB, Brown D, Oelschlager DK, Waterbor JW, Marshall ME, Srivastava S, …, Grizzle WE (1996) Elevated serum levels of p105erbB-2 in patients with advanced-stage prostatic adenocarcinoma. Int J Cancer 69(5):398–402Google Scholar
  30. 30.
    Bharti AC, Aggarwal BB (2002) Nuclear factor-kappa B and cancer: its role in prevention and therapy. Biochem Pharmacol 64(5):883–888PubMedCrossRefGoogle Scholar
  31. 31.
    Beg AA, Baltimore D (1996) An essential role for NF-κB in preventing TNF-alpha-induced cell death. Science 274(5288):782PubMedCrossRefGoogle Scholar
  32. 32.
    Sun SC, Yamaoka S (2005) Activation of NF-κB by HTLV-I and implications for cell transformation. Oncogene 24(39):5952–5964PubMedCrossRefGoogle Scholar
  33. 33.
    Tang H, Oishi N, Kaneko S, Murakami S (2006a) Molecular functions and biological roles of hepatitis B virus x protein. Cancer Sci 97(10):977–983PubMedCrossRefGoogle Scholar
  34. 34.
    Kuper H, Adami HO, Trichopoulos D (2000) Infections as a major preventable cause of human cancer. J Intern Med 248(3):171–183PubMedCrossRefGoogle Scholar
  35. 35.
    Greten FR, Eckmann L, Greten TF, Park JM, Li, Z. W., Egan LJ, …, Karin M (2004) IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118(3):285–296Google Scholar
  36. 36.
    Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, …, Ben-Neriah Y (2004) NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431(7007):461–466Google Scholar
  37. 37.
    Ruland J, Duncan GS, Elia A, del Barco Barrantes I, Nguyen L, Plyte S, …, Mak TW (2001) Bcl10 is a positive regulator of antigen receptor–induced activation of NF-κ B and neural tube closure. Cell 104(1):33–42Google Scholar
  38. 38.
    Karin M (2006) Nuclear factor-κB in cancer development and progression. Nature 441(7092):431–436PubMedCrossRefGoogle Scholar
  39. 39.
    Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3(9):745–756PubMedCrossRefGoogle Scholar
  40. 40.
    Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, …, Karin M (2008) NF-&kgr; B links innate immunity to the hypoxic response through transcriptional regulation of HIF-1&agr. Nature 453(7196):807–811Google Scholar
  41. 41.
    Helbig G, Christopherson KW 2nd, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, Broxmeyer HE, Nakshatri H (2003) NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem 278(24):21631–21638PubMedCrossRefGoogle Scholar
  42. 42.
    Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, …, Weinberg RA (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927–939Google Scholar
  43. 43.
    Huber MA, Beug H, Wirth T (2004) Epithelial-mesenchymal transition: NF-κB takes center stage. Cell Cycle 3(12):1477–1480PubMedCrossRefGoogle Scholar
  44. 44.
    Tabruyn SP, Griffioen AW (2007) A new role for NF B in angiogenesis inhibition. Cell Death Differ 14(8):1393–1397PubMedCrossRefGoogle Scholar
  45. 45.
    Knecht H, Berger C, Rothenberger S, Odermatt BF, Brousset P (2001) The role of Epstein-Barr virus in neoplastic transformation. Oncology 60(4):289–302PubMedCrossRefGoogle Scholar
  46. 46.
    Lei HY, Zhao XL (2007) Clinical significance of NF-kappaB continual activity and expression of WT1 and MDR1 in acute nonlymphocytic leukemia. Zhongguo shi yan xue ye xue za zhi/Zhongguo bing li sheng li xue hui= J Exp Hematol/Chin Assoc Pathophysiol 15(2):253–257Google Scholar
  47. 47.
    Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ, Sledge GW (1997) Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol 17(7):3629–3639PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Sovak MA, Bellas RE, Kim DW, Zanieski GJ, Rogers AE, Traish AM, Sonenshein GE (1997) Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. J Clin Investig 100(12):2952PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Ahmed KM, Cao N, Li JJ (2006) HER-2 and NF-κB as the targets for therapy-resistant breast cancer. Anticancer Res 26(6B):4235–4243PubMedPubMedCentralGoogle Scholar
  50. 50.
    Nair A, Venkatraman M, Maliekal TT, Nair B, Karunagaran D (2003) NF-κB is constitutively activated in high-grade squamous intraepithelial lesions and squamous cell carcinomas of the human uterine cervix. Oncogene 22(1):50–58PubMedCrossRefGoogle Scholar
  51. 51.
    Shehata MF (2005) Rel/nuclear factor-kappa B apoptosis pathways in human cervical cancer cells. Cancer Cell Int 5(1):1CrossRefGoogle Scholar
  52. 52.
    Ramdass B, Maliekal TT, Lakshmi S, Rehman M, Rema P, Nair P, …, Pillai MR (2007) Coexpression of Notch1 and NF-κB signaling pathway components in human cervical cancer progression. Gynecol Oncol 104(2):352–361Google Scholar
  53. 53.
    Dejardin E, Deregowski V, Chapelier M, Jacobs N, Gielen J, Merville MP, Bours V (1999) Regulation of NF-κB activity by IkB-related proteins in adenocarcinoma cells. Oncogene 18(16):2567–2578PubMedCrossRefGoogle Scholar
  54. 54.
    Huang S, Robinson JB, DeGuzman A, Bucana CD, Fidler IJ (2000) Blockade of nuclear factor-κB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res 60(19):5334–5339PubMedGoogle Scholar
  55. 55.
    Seppänen M, Vihko KK (2000) Activation of transcription factor NF-κB by growth inhibitory cytokines in vulvar carcinoma cells. Immunol Lett 74(2):103–109PubMedCrossRefGoogle Scholar
  56. 56.
    Huang S, Pettaway CA, Uehara H, Bucana CD, Fidler IJ (2001) Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 20(31):4188PubMedCrossRefGoogle Scholar
  57. 57.
    Palayoor ST, Youmell MY, Calderwood SK, Coleman CN, Price BD (1999a) Constitutive activation of IkB kinase a and NF-κB in prostate cancer cells is inhibited by ibuprofen. Oncogene 18(51):7389–7394PubMedCrossRefGoogle Scholar
  58. 58.
    Fradet V, Lessard L, Bégin LR, Karakiewicz P, Masson AMM, Saad F (2004) Nuclear factor-κB nuclear localization is predictive of biochemical recurrence in patients with positive margin prostate cancer. Clin Cancer Res 10(24):8460–8464PubMedCrossRefGoogle Scholar
  59. 59.
    Lessard L, Karakiewicz PI, Bellon-Gagnon P, Alam-Fahmy M, Ismail HA, Mes-Masson AM, Saad F (2006) Nuclear localization of nuclear factor-κB p65 in primary prostate tumors is highly predictive of pelvic lymph node metastases. Clin Cancer Res 12(19):5741–5745PubMedCrossRefGoogle Scholar
  60. 60.
    Paule B, Terry S, Kheuang L, Soyeux P, Vacherot F, de la Taille A (2007) The NF-κB/IL-6 pathway in metastatic androgen-independent prostate cancer: new therapeutic approaches? World J Urol 25(5):477–489PubMedCrossRefGoogle Scholar
  61. 61.
    Oya M, Ohtsubo M, Takayanagi A, Tachibana M, Shimizu N, Murai M (2001) Constitutive activation of nuclear factor-kB prevents TRAIL-induced apoptosis in renal cancer cells. Oncogene 20(3888):3896Google Scholar
  62. 62.
    Horiguchi Y, Kuroda K, Nakashima J, Murai M, Umezawa K (2003) Antitumor effect of a novel nuclear factor-κB activation inhibitor in bladder cancer cells. Expert Rev Anticancer Ther 3(6):793–798PubMedCrossRefGoogle Scholar
  63. 63.
    Kadhim HS, TI AL-J, Tawfik MS (2006) Possible role of nuclear factor kB detected by in situ hybridization in the pathogenesis of transitional cell carcinoma of the bladder. J Med Liban 54:96–99Google Scholar
  64. 64.
    Levidou G, Korkolopoulou P, Nikiteas N, Tzanakis N, Thymara I, Saetta AA, …, Patsouris E (2007) Expression of nuclear factor κB in human gastric carcinoma: relationship with IκBa and prognostic significance. Virchows Archiv 450(5):519–527Google Scholar
  65. 65.
    Tichelaar JW, Zhang Y, Lam S, Anderson MW (2004) Activation of the Akt/nuclear factor-κB signaling Axis in developing lung neoplasia. Chest J 125(5_suppl):153S–153SCrossRefGoogle Scholar
  66. 66.
    Tang X, Liu D, Shishodia S, Ozburn N, Behrens C, Lee JJ, …, Wistuba II (2006b) Nuclear factor-κB (nf-κB) is frequently expressed in lung cancer and preneoplastic lesions. Cancer 107(11):2637–2646Google Scholar
  67. 67.
    Zhang D, Jin X, Wang F, Wang S, Deng C, Gao Z, Guo C (2007) Combined prognostic value of both RelA and IκB-α expression in human non–small cell lung cancer. Ann Surg Oncol 14(12):3581–3592PubMedCrossRefGoogle Scholar
  68. 68.
    Motadi LR, Misso NL, Dlamini Z, Bhoola KD (2007) Molecular genetics and mechanisms of apoptosis in carcinomas of the lung and pleura: therapeutic targets. Int Immunopharmacol 7(14):1934–1947PubMedCrossRefGoogle Scholar
  69. 69.
    Stathopoulos GT, Sherrill TP, Han W, Sadikot RT, Yull FE, Blackwell TS, Fingleton B (2008) Host nuclear factor-κB activation potentiates lung cancer metastasis. Mol Cancer Res 6(3):364–371PubMedCrossRefGoogle Scholar
  70. 70.
    Bertino P, Marconi A, Palumbo L, Bruni BM, Barbone D, Germano S, …, Gaudino G (2007) Erionite and asbestos differently cause transformation of human mesothelial cells. Int J Cancer 121(1):12–20Google Scholar
  71. 71.
    Carbone M, Bedrossian CW (2006) The pathogenesis of mesothelioma. In Seminars in diagnostic pathology, 23(1). WB Saunders, p 56–60Google Scholar
  72. 72.
    Zhang Z, Ma J, Li N, Sun N, Wang C (2006) Expression of nuclear factor-κB and its clinical significance in nonsmall-cell lung cancer. Ann Thorac Surg 82(1):243–248PubMedCrossRefGoogle Scholar
  73. 73.
    Tew GW, Lorimer EL, Berg TJ, Zhi H, Li R, Williams CL (2008) SmgGDS regulates cell proliferation, migration, and NF-κB transcriptional activity in non-small cell lung carcinoma. J Biol Chem 283(2):963–976PubMedCrossRefGoogle Scholar
  74. 74.
    Jin X, Wang Z, Qiu L, Zhang D, Guo Z, Gao Z, …, Guo C (2008) Potential biomarkers involving IKK/RelA signal in early stage non-small cell lung cancer. Cancer Sci 99(3):582–589Google Scholar
  75. 75.
    Tai DI, Tsai SL, Chang YH, Huang SN, Chen TC, Chang KS, Liaw YF (2000) Constitutive activation of nuclear factor κB in hepatocellular carcinoma. Cancer 89(11):2274–2281PubMedCrossRefGoogle Scholar
  76. 76.
    Arsura M, Cavin LG (2005) Nuclear factor-κB and liver carcinogenesis. Cancer Lett 229(2):157–169PubMedCrossRefGoogle Scholar
  77. 77.
    Qiao L, Zhang H, Yu J, Francisco R, Dent P, Ebert MP, ... & Farrell G (2006) Constitutive activation of NF-κB in human hepatocellular carcinoma: evidence of a cytoprotective role. Hum Gene Ther 17(3):280–290Google Scholar
  78. 78.
    Seki E, Brenner DA (2007) The role of NF-κB in hepatocarcinogenesis: promoter or suppressor? J Hepatol 47(2):307–309PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ (1999) The nuclear factor-κB RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 5(1):119–127PubMedGoogle Scholar
  80. 80.
    Sclabas GM, Fujioka S, Schmidt C, Evans DB, Chiao PJ (2003) NF-κB in pancreatic cancer. Int J Gastrointest Cancer 33(1):15–26PubMedCrossRefGoogle Scholar
  81. 81.
    Xiong HQ (2004) Molecular targeting therapy for pancreatic cancer. Cancer Chemother Pharmacol 54(1):S69–S77PubMedGoogle Scholar
  82. 82.
    Jackson L, Evers BM (2006) Chronic inflammation and pathogenesis of GI and pancreatic cancers. In The link between inflammation and cancer. Springer US, pp 39–65Google Scholar
  83. 83.
    Sutter AP, Zeitz M, Scherübl H (2004) Recent results in understanding molecular pathways in the medical treatment of esophageal and gastric cancer. Oncol Res Treat 27(1):17–21CrossRefGoogle Scholar
  84. 84.
    Lee BL, Lee HS, Jung J, Cho SJ, Chung HY, Kim WH, …, Nam SY (2005) Nuclear factor-κB activation correlates with better prognosis and Akt activation in human gastric cancer. Clin Cancer Res 11(7):2518–2525Google Scholar
  85. 85.
    Abdel-Latif MM, Kelleher D, Reynolds JV (2009) Potential role of NF-κB in esophageal adenocarcinoma: as an emerging molecular target. J Surg Res 153(1):172–180PubMedCrossRefGoogle Scholar
  86. 86.
    Zhu J, Hu G, Sun Y (2004) Expression and significance of nuclear factor kB in laryngeal carcinoma [article in Chinese]. Lin Chuang Er Bi Yan Hou Ke Za Zhi 18(745–6):766Google Scholar
  87. 87.
    Pan S, Tao Z, Wu L, Xiao B, Chen S (2005) Nuclear factor kappaB/p65 and cyclooxygenase-2 expression and clinic significance in human laryngeal squamous cell carcinoma. Lin Chuang Er Bi Yan Jou Ke Za Zhi 19(12):535–537Google Scholar
  88. 88.
    Sasaki N, Morisaki T, Hashizume K, Yao T, Tsuneyoshi M, Noshiro H, …, Katano M (2001) Nuclear factor-κB p65 (RelA) transcription factor is constitutively activated in human gastric carcinoma tissue. Clin Cancer Res 7(12):4136–4142Google Scholar
  89. 89.
    Wu L, Pu Z, Feng J, Li G, Zheng Z, Shen W (2008) The ubiquitin-proteasome pathway and enhanced activity of NF-κB in gastric carcinoma. J Surg Oncol 97(5):439–444PubMedCrossRefGoogle Scholar
  90. 90.
    Lind DS, Hochwald SN, Malaty J, Rekkas S, Hebig P, Mishra G, …, MacKay S (2001) Nuclear factor-κB is upregulated in colorectal cancer. Surgery 130(2):363–369Google Scholar
  91. 91.
    Schottelius AJ, Dinter H (2006) Cytokines, NF-κB, microenvironment, intestinal inflammation and cancer. In The link between inflammation and cancer. Springer US, p 67–87Google Scholar
  92. 92.
    Aranha MM, Borralho PM, Ravasco P, Moreira da Silva IB, Correia L, Fernandes A, ..., Rodrigues CMP (2007) NF-κB and apoptosis in colorectal tumourigenesis. Eur J Clin Investig 37(5):416–424Google Scholar
  93. 93.
    Visconti R, Cerutti J, Battista S, Fedele M, Trapasso F, Zeki K, …, Santoro M (1997) Expression of the neoplastic phenotype by human thyroid carcinoma cell lines requires NF-κB p65 protein expression. Oncogene 15(16):1987–1994Google Scholar
  94. 94.
    Pacifico F, Leonardi A (2006) NF-κB in solid tumors. Biochem Pharmacol 72(9):1142–1152PubMedCrossRefGoogle Scholar
  95. 95.
    Gombos K, Szele E, Kiss I, Varjas T, Puskás L, Kozma L, …, Ember I (2007) Characterization of microarray gene expression profiles of early stage thyroid tumours. Cancer Genomics-Proteomics 4(6):403–409Google Scholar
  96. 96.
    Corbetta S, Vicentini L, Ferrero S, Lania A, Mantovani G, Cordella D, …, Spada A (2005) Activity and function of the nuclear factor kappaB pathway in human parathyroid tumors. Endocr-Relat Cancer 12(4):929–937Google Scholar
  97. 97.
    Yang J, Richmond A (2001) Constitutive IκB kinase activity correlates with nuclear factor-κB activation in human melanoma cells. Cancer Res 61(12):4901–4909PubMedGoogle Scholar
  98. 98.
    Van den Oord JJ, Sarasin A, Winnepenninckx V, Spatz A (2007) Expression profiling of melanoma cell lines: in search of a progression-related molecular signatureGoogle Scholar
  99. 99.
    Ondrey FG, Dong G, Sunwoo J, Chen Z, Wolf JS, Crowl-Bancroft CV, Van Waes C (1999) Constitutive activation of transcription factors NF-κB, 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
  100. 100.
    Chung CH, Parker JS, Ely K, Carter J, Yi Y, Murphy BA, …, Levy S (2006) Gene expression profiles identify epithelial-to-mesenchymal transition and activation of nuclear factor-κB signaling as characteristics of a high-risk head and neck squamous cell carcinoma. Cancer Res 66(16):8210–8218Google Scholar
  101. 101.
    Allen CT, Ricker JL, Chen Z, Van Waes C (2007) Role of activated nuclear factor-κB in the pathogenesis and therapy of squamous cell carcinoma of the head and neck. Head Neck 29(10):959–971PubMedCrossRefGoogle Scholar
  102. 102.
    Jackson-Bernitsas DG, Ichikawa H, Takada Y, Myers JN, Lin XL, Darnay BG, …, Aggarwal BB (2007) Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-κB activation and proliferation in human head and neck squamous cell carcinoma. Oncogene 26(10):1385–1397Google Scholar
  103. 103.
    Pallares J, Martínez-Guitarte JL, Dolcet X, Llobet D, Rue M, Palacios J, Matias-Guiu X (2004) Abnormalities in the NF-κB family and related proteins in endometrial carcinoma. J Pathol 204(5):569–577PubMedCrossRefGoogle Scholar
  104. 104.
    Domenyuk VP, Litovkin KV, Verbitskaya TG, Dubinina VG, Bubnov VV (2007) Identification of new DNA markers of endometrial cancer in patients from the Ukrainian population. Exp Oncol 29(2):152–155PubMedGoogle Scholar
  105. 105.
    Kovalenko A, Chable-Bessia C, Cantarella G, Israël A, Wallach D, Courtois G (2003) The tumour suppressor CYLD negatively regulates NF-κB signalling by deubiquitination. Nature 424(6950):801–805PubMedCrossRefGoogle Scholar
  106. 106.
    Brummelkamp TR, Nijman SM, Dirac AM, Bernards R (2003) Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB. Nature 424(6950):797–801PubMedCrossRefGoogle Scholar
  107. 107.
    Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G (2003) CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members. Nature 424(6950):793–796PubMedCrossRefGoogle Scholar
  108. 108.
    Chen F (2005b) Is NF-κB a culprit in type 2 diabetes? Biochem Biophys Res Commun 332(1):1–3PubMedCrossRefGoogle Scholar
  109. 109.
    Nakayama H, Ikebe T, Beppu M, Shirasuna K (2001) High expression levels of nuclear factor κB, IκB kinase α and Akt kinase in squamous cell carcinoma of the oral cavity. Cancer 92(12):3037–3044PubMedCrossRefGoogle Scholar
  110. 110.
    Bindhu OS, Ramadas K, Sebastian P, Pillai MR (2006) High expression levels of nuclear factor kappa B and gelatinases in the tumorigenesis of oral squamous cell carcinoma. Head Neck 28(10):916–925PubMedCrossRefGoogle Scholar
  111. 111.
    Mishra A, Bharti AC, Varghese P, Saluja D, Das BC (2006) Differential expression and activation of NF-κB family proteins during oral carcinogenesis: role of high risk human papillomavirus infection. Int J Cancer 119(12):2840–2850PubMedCrossRefGoogle Scholar
  112. 112.
    Sawhney M, Rohatgi N, Kaur J, Shishodia S, Sethi G, Gupta SD, …, Ralhan R (2007) Expression of NF-κB parallels COX-2 expression in oral precancer and cancer: association with smokeless tobacco. Int J Cancer 120(12):2545–2556Google Scholar
  113. 113.
    Ruan M, Ji T, Yang W, Duan W, Zhou X, He J, …, Zhang C (2008) Growth inhibition and induction of apoptosis in human oral squamous cell carcinoma Tca-8113 cell lines by shikonin was partly through the inactivation of NF-κB pathway. Phytother Res 22(3):407–415Google Scholar
  114. 114.
    Hayashi S, Yamamoto M, Ueno Y, Ikeda K, Ohshima K, Soma GI, Fukushima T (2001) Expression of nuclear factor-. KAPPA. B, tumor necrosis factor receptor type 1, and c-Myc in human astrocytomas. Neurol Med Chir 41(4):187–195CrossRefGoogle Scholar
  115. 115.
    Garkavtsev I, Kozin SV, Chernova O, Xu L, Winkler F, Brown E, …, Jain RK (2004) The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis. Nature 428(6980):328–332Google Scholar
  116. 116.
    Zenali MJ, Zhang PL, Bendel AE, Brown RE (2009) Morphoproteomic confirmation of constitutively activated mTOR, ERK, and NF-kappaB pathways in Ewing family of tumors. Ann Clin Lab Sci 39(2):160–166PubMedGoogle Scholar
  117. 117.
    Widera D, Kaus A, Kaltschmidt C, Kaltschmidt B (2008) Neural stem cells, inflammation and NF-κB: basic principle of maintenance and repair or origin of brain tumours? J Cell Mol Med 12(2):459–470PubMedCrossRefGoogle Scholar
  118. 118.
    Raychaudhuri B, Han Y, Lu T, Vogelbaum MA (2007) Aberrant constitutive activation of nuclear factor κB in glioblastoma multiforme drives invasive phenotype. J Neuro-Oncol 85(1):39–47CrossRefGoogle Scholar
  119. 119.
    Smith D, Shimamura T, Barbera S, Bejcek BE (2008) NF-κB controls growth of glioblastomas/astrocytomas. Mol Cell Biochem 307(1–2):141–147PubMedGoogle Scholar
  120. 120.
    Bargou RC, Leng C, Krappmann D, Emmerich F, Mapara MY, Bommert K, …, Dorken B (1996) High-level nuclear NF-kappa B and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells. Blood 87(10):4340–4347Google Scholar
  121. 121.
    Bargou RC, Emmerich F, Krappmann D, Bommert K, Mapara MY, Arnold W, …, Dörken B (1997) Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin’s disease tumor cells. J Clin Invest 100(12):2961Google Scholar
  122. 122.
    Staudt LM (2000) The molecular and cellular origins of Hodgkin’s disease. J Exp Med 191(2):207–212PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Kordes U, Krappmann D, Heissmeyer V, Ludwig WD, Scheidereit C (2000) Transcription factor NF-κB is constitutively activated in acute lymphoblastic leukemia cells. Leukemia 14(3):399–402PubMedCrossRefGoogle Scholar
  124. 124.
    Munzert G, Kirchner D, Ottmann O, Bergmann L, Schmid RM (2004) Constitutive NF-κB/Rel activation in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Leuk Lymphoma 45(6):1181–1184PubMedCrossRefGoogle Scholar
  125. 125.
    Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA, …, Jordan CT (2001) Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98(8):2301–2307Google Scholar
  126. 126.
    Fabre C, Carvalho G, Tasdemir E, Braun T, Ades L, Grosjean J, …, Fenaux P (2007) NF-κB inhibition sensitizes to starvation-induced cell death in high-risk myelodysplastic syndrome and acute myeloid leukemia. Oncogene 26(28):4071–4083Google Scholar
  127. 127.
    Arima N, Tei C (2001) HTLV-I tax related dysfunction of cell cycle regulators and oncogenesis of Radult T cell leukemia. Leuk Lymphoma 40(3–4):267–278PubMedCrossRefGoogle Scholar
  128. 128.
    Horie R, Watanabe T, Umezawa K (2006) Blocking NF-kappaB as a potential strategy to treat adult T-cell leukemia/lymphoma. Drug News Perspect 19(4):201–209PubMedCrossRefGoogle Scholar
  129. 129.
    Furman RR, Asgary Z, Mascarenhas JO, Liou HC, Schattner EJ (2000) Modulation of NF-κB activity and apoptosis in chronic lymphocytic leukemia B cells. J Immunol 164(4):2200–2206PubMedCrossRefGoogle Scholar
  130. 130.
    Pickering BM, De Mel S, Lee M, Howell M, Habens F, Dallman CL, Johnson PWM (2007) Pharmacological inhibitors of NF-κB accelerate apoptosis in chronic lymphocytic leukaemia cells. Oncogene 26(8):1166–1177PubMedCrossRefGoogle Scholar
  131. 131.
    Hewamana S, Alghazal S, Lin TT, Clement M, Jenkins C, Guzman ML, …, Pratt G (2008) The NF-κB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target. Blood 111(9):4681–4689Google Scholar
  132. 132.
    Berenson JR, Ma HM, Vescio R (2001) The role of nuclear factor-κB in the biology and treatment of multiple myeloma. In Seminars in oncology (Vol. 28, No. 6). WB Saunders, pp 626–633Google Scholar
  133. 133.
    Gilmore TD (2007) Multiple myeloma: lusting for NF-κB. Cancer Cell 12(2):95–97PubMedCrossRefGoogle Scholar
  134. 134.
    Gilmore T, Gapuzan ME, Kalaitzidis D, Starczynowski D (2002) Rel/NF-κB/IκB signal transduction in the generation and treatment of human cancer. Cancer Lett 181(1):1–9PubMedCrossRefGoogle Scholar
  135. 135.
    Sagaert X, De Wolf-Peeters C, Noels H, Baens M (2007) The pathogenesis of MALT lymphomas: where do we stand? Leukemia 21(3):389–396PubMedCrossRefGoogle Scholar
  136. 136.
    Inagaki H (2007) Mucosa-associated lymphoid tissue lymphoma: molecular pathogenesis and clinicopathological significance. Pathol Int 57(8):474–484PubMedCrossRefGoogle Scholar
  137. 137.
    Du MQ (2007) MALT lymphoma: recent advances in aetiology and molecular genetics. J Clin Exp Hematop 47(2):31–42PubMedCrossRefGoogle Scholar
  138. 138.
    Agathocleous A, Rohatiner A, Rule S, Hunter H, Kerr JP, Neeson SM, …, Radford J (2010) Weekly versus twice weekly bortezomib given in conjunction with rituximab, in patients with recurrent follicular lymphoma, mantle cell lymphoma and Waldenström macroglobulinaemia. Br J Haematol 151(4):346–353Google Scholar
  139. 139.
    Gupta SC, Sundaram C, Reuter S, Aggarwal BB (2010) Inhibiting NF-κB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta (BBA)-Gene Regul Mech 1799(10):775–787CrossRefGoogle Scholar
  140. 140.
    Wilczynski J, Duechler M, Czyz M (2011) Targeting NF-κB and HIF-1 pathways for the treatment of cancer: part II. Arch Immunol Ther Exp 59(4):301–307CrossRefGoogle Scholar
  141. 141.
    García MG, Alaniz L, Lopes EC, Blanco G, Hajos SE, Alvarez E (2005) Inhibition of NF-κB activity by BAY 11-7082 increases apoptosis in multidrug resistant leukemic T-cell lines. Leuk Res 29(12):1425–1434PubMedCrossRefGoogle Scholar
  142. 142.
    Yang J, Amiri KI, Burke JR, Schmid JA, Richmond A (2006) BMS-345541 targets inhibitor of κB kinase and induces apoptosis in melanoma: involvement of nuclear factor κB and mitochondria pathways. Clin Cancer Res 12(3):950–960PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Choo M, Sakurai H, Kim D, Saiki I (2008) A ginseng saponin metabolite suppresses tumor necrosis factor-alpha-promoted metastasis by suppressing nuclear factor-kappa B signaling in murine colon cancer cells. Oncol Rep 19(3):595PubMedGoogle Scholar
  144. 144.
    Ravaud A, Cerny T, Terret C, Wanders J, Bui BN, Hess D, …, Twelves C (2005) Phase I study and pharmacokinetic of CHS-828, a guanidino-containing compound, administered orally as a single dose every 3weeks in solid tumours: an ECSG/EORTC study. Euro J Cancer 41(5):702–707Google Scholar
  145. 145.
    Podar K, Anderson KC (2011) Emerging therapies targeting tumor vasculature in multiple myeloma and other hematologic and solid malignancies. Curr Cancer Drug Targets 11(9):1005–1024PubMedCrossRefGoogle Scholar
  146. 146.
    Gasparian AV, Guryanova OA, Chebotaev DV, Shishkin AA, Yemelyanov AY, Budunova IV (2009) Targeting transcription factor NFκB: comparative analysis of proteasome and IKK inhibitors. Cell Cycle 8(10):1559–1566PubMedCrossRefGoogle Scholar
  147. 147.
    Mabuchi S, Ohmichi M, Nishio Y, Hayasaka T, Kimura A, Ohta T, …, Sakata M (2004) Inhibition of NFκB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models. J Biol Chem279(22):23477–23485Google Scholar
  148. 148.
    Baron JA (2009) Aspirin and NSAIDs for the prevention of colorectal cancer. In Cancer prevention II. Springer Berlin Heidelberg, pp 223–229Google Scholar
  149. 149.
    Rahman I, Biswas SK, Kirkham PA (2006) Regulation of inflammation and redox signaling by dietary polyphenols. Biochem Pharmacol 72(11):1439–1452PubMedCrossRefGoogle Scholar
  150. 150.
    Lee CT, Seol JY, Lee SY, Park KH, Han SJ, Yoo CG, …, Kim YW (2003) The effect of adenovirus-IκBα transduction on the chemosensitivity of lung cancer cell line with resistance to cis-diamminedichloroplatinum (II)(cisplatin) and doxorubicin (adriamycin). Lung Cancer 41(2):199–206Google Scholar
  151. 151.
    Sethi G, Sung B, Aggarwal BB (2008) Nuclear factor-κB activation: from bench to bedside. Exp Biol Med 233(1):21–31CrossRefGoogle Scholar
  152. 152.
    Uetsuka H, Haisa M, Kimura M, Gunduz M, Kaneda Y, Ohkawa T, …, Matsuoka J (2003) Inhibition of inducible NF-κB activity reduces chemoresistance to 5-fluorouracil in human stomach cancer cell line. Exp Cell Res 289(1):27–35Google Scholar
  153. 153.
    Wajant H, Scheurich P (2011) TNFR1-induced activation of the classical NF-κB pathway. FEBS J 278(6):862–876PubMedCrossRefGoogle Scholar
  154. 154.
    Pierce JW, Schoenleber R, Jesmok G, Best J, Moore SA, Collins T, Gerritsen ME (1997) Novel inhibitors of cytokine-induced IκBα phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo. J Biol Chem 272(34):21096–21103PubMedCrossRefGoogle Scholar
  155. 155.
    Hideshima T, Neri P, Tassone P, Yasui H, Ishitsuka K, Raje N, …, Munshi N (2006) MLN120B, a novel IκB kinase β inhibitor, blocks multiple myeloma cell growth in vitro and in vivo. Clin Cancer Res 12(19):5887–5894Google Scholar
  156. 156.
    Podolin PL, Callahan JF, Bolognese BJ, Li YH, Carlson K, Davis TG, …, Roshak AK (2005) Attenuation of murine collagen-induced arthritis by a novel, potent, selective small molecule inhibitor of IκB kinase 2, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide), occurs via reduction of proinflammatory cytokines and antigen-induced T cell proliferation. J Pharmacol Exp Ther 312(1):373–381Google Scholar
  157. 157.
    Du Z, Whitt MA, Baumann J, Garner JM, Morton CL, Davidoff AM, Pfeffer LM (2012) Inhibition of type I interferon-mediated antiviral action in human glioma cells by the IKK inhibitors BMS-345541 and TPCA-1. J Interferon Cytokine Res 32(8):368–377PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Tanaka A, Konno M, Muto S, Kambe N, Morii E, Nakahata T, …, Matsuda H (2005) A novel NF-κB inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors. Blood 105(6):2324–2331Google Scholar
  159. 159.
    Sugita A, Ogawa H, Azuma M, Muto S, Honjo A, Yanagawa H, …,Sone S (2008) Antiallergic and anti-inflammatory effects of a novel IκB kinase β inhibitor, IMD-0354, in a mouse model of allergic inflammation. Int Arch Allergy Immunol 148(3):186–198Google Scholar
  160. 160.
    Waelchli R, Bollbuck B, Bruns C, Buhl T, Eder J, Feifel R, …, Schlapbach A (2006) Design and preparation of 2-benzamido-pyrimidines as inhibitors of IKK. Bioorg Med Chem Lett 16(1):108–112Google Scholar
  161. 161.
    Murugan A et al (2014) Exploiting the differential Reactivities of halogen atoms: development of a scalable route to IKK2 inhibitor AZD3264. Org Process Res Dev 18(5):646–651CrossRefGoogle Scholar
  162. 162.
    Shishodia S, Sethi G, Konopleva M, Andreeff M, Aggarwal BB (2006) A synthetic triterpenoid, CDDO-Me, inhibits IκBα kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor κB–regulated gene products in human leukemic cells. Clin Cancer Res 12(6):1828–1838PubMedCrossRefGoogle Scholar
  163. 163.
    Gupta SV, Hertlein E, Lu Y, Sass EJ, Lapalombella R, Chen TL, …, Byrd JC (2013) The proteasome inhibitor carfilzomib functions independently of p53 to induce cytotoxicity and an atypical NF-κB response in chronic lymphocytic leukemia cells. Clin Cancer Res 19(9):2406–2419Google Scholar
  164. 164.
    Yamamoto Y, Yin MJ, Lin KM, Gaynor RB (1999) Sulindac inhibits activation of the NF-κB pathway. J Biol Chem 274(38):27307–27314PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd 2017

Authors and Affiliations

  • Prudhvi Lal Bhukya
    • 1
  • Rongala Laxmivandana
    • 2
  • Gopinath Meenakshi Sundaram
    • 3
  1. 1.National Institute of VirologyPuneIndia
  2. 2.ICAR-IIABRanchiIndia
  3. 3.Institute of Medical BiologyAgency for Science Technology & Research (A*STAR)SingaporeSingapore

Personalised recommendations