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NF-κB in cancer: from innocent bystander to major culprit

Key Points

  • Nuclear factor of κB (NF-κB) is a transcriptional regulator that is made up of different protein dimers that bind a common sequence motif known as the κB site.

  • Although NF-κB target genes have been most intensely studied for their involvement in immunity and inflammation, this transcription factor also regulates cell proliferation, apoptosis and cell migration. Therefore, it is not surprising that NF-κB has been shown to be constitutively activated in several types of cancer cell.

  • NF-κB activity is tightly controlled by several regulatory proteins, and disruption of this process has been associated with various haematological malignancies, as well as epithelial tumours such as breast cancer.

  • A causal connection between inflammation and cancer has been suspected for many years. Because NF-κB becomes activated in response to inflammatory stimuli and its constitutive activation has been associated with cancer, NF-κB might also serve as the missing link between these two processes. Numerous inhibitors of NF-κB are therefore under development or have been developed.

  • Because of the widespread importance of this factor, it has been difficult to develop NF-κB inhibitors that act specifically in cancer cells. Learning more about the complicated process of NF-κB regulation should lead to better therapeutic approaches to target the factor in specific cell types.


Nuclear factor of κB (NF-κB) is a sequence-specific transcription factor that is known to be involved in the inflammatory and innate immune responses. Although the importance of NF-κB in immunity is undisputed, recent evidence indicates that NF-κB and the signalling pathways that are involved in its activation are also important for tumour development. NF-κB should therefore receive as much attention from cancer researchers as it has already from immunologists.

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Figure 1: The IKK complex controls two distinct NF-κB activation pathways.
Figure 2: NF-κB contributes to the induction of four classes of genes.
Figure 3: Different mechanisms by which NF-κB activation can contribute to leukaemia and lymphogenesis.
Figure 4: Signalling pathways that stimulate the proliferation of mammary epithelial cells by induction of cyclin D1 gene transcription.
Figure 5: Role of NF-κB in gastric and colorectal cancers.


  1. Ghosh, S., May, M. J. & Kopp, E. B. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16, 225–260 (1998).

    CAS  PubMed  Google Scholar 

  2. Gilmore, T. D. Multiple mutations contribute to the oncogenicity of the retroviral oncoprotein v-Rel. Oncogene 18, 6925–6937 (1999).

    CAS  PubMed  Google Scholar 

  3. Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18, 621–663 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Li, Z.-W. et al. The IKKβ subunit of IκB kinase (IKK) is essential for NF-κB activation and prevention of apoptosis. J. Exp. Med. 189, 1839–1845 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Solan, N. J., Miyoshi, H., Bren, G. D. & Paya, C. V. RelB cellular regulation and transcriptional activity are regulated by p100. J. Biol. Chem. 277, 1405–1418 (2002).

    CAS  PubMed  Google Scholar 

  6. Senftleben, U. et al. Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293, 1495–1499 (2001).

    CAS  PubMed  Google Scholar 

  7. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).Shows how IKKα activates a second NF-κB pathway by NF-κB2 processing from p100 to p52 in response to NIK stimulation — a function that is not provided by IKKβ.

    CAS  PubMed  Google Scholar 

  8. Xiao, G. et al. Retroviral oncoprotein Tax induces processing of NF-κB2/p100 in T cells: evidence for the involvement of IKKα. Oncogene 20, 6805–6815 (2001).

    CAS  Google Scholar 

  9. Mosialos, G. The role of Rel/NF-κB proteins in viral oncogenesis and the regulation of viral transcription. Semin. Cancer Biol. 8, 121–129 (1997).

    CAS  PubMed  Google Scholar 

  10. Guttridge, D. C., Albanese, C., Reuther, J. Y., Pestell, R. G. & Baldwin, A. S. Jr., NF-κB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol. Cell Biol. 19, 5785–5799 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hinz, M. et al. NF-κB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol. Cell Biol. 19, 2690–2698 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Cao, Y. et al. IKKα provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell 107, 763–775 (2001).Reports that IKKα kinase activity is required for mammary-gland development during pregnancy, and it is an essential mediator for cyclin D1 induction by NF-κB in response to pregnancy signals.

    CAS  PubMed  Google Scholar 

  13. Beg, A. A. & Baltimore, D. An essential role for NF-κB in preventing TNF-α-induced cell death. Science 274, 782–784 (1996).

    CAS  PubMed  Google Scholar 

  14. Liu, Z.-G., Hu, H., Goeddel, D. V. & Karin, M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis, while NF-κB activation prevents cell death. Cell 87, 565–576 (1996).

    CAS  PubMed  Google Scholar 

  15. Van Antwerp, D. J., Martin, S. J., Kafri, T., Green, D. R. & Verma, I. M. Suppression of TNFα-induced apoptosis by NF-κB. Science 274, 787–789 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Wang, C.-Y., Mayo, M. W. & Baldwin, A. S. Jr., TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB. Science 274, 784–787 (1996).

    CAS  PubMed  Google Scholar 

  17. Karin, M. & Lin, A. NF-κB at the crossroad of Life and Death. Nature Immunol. 3, 221–227 (2002).

    CAS  Google Scholar 

  18. Wang, C. Y., Cusack, J. C. Jr, Liu, R. & Baldwin, A. S. Jr. Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-κB. Nature Med. 5, 412–417 (1999).NF-κB activation during cancer therapy is the principle mechanism of tumour chemoresistance. This article shows that inhibition of NF-κB sensitizes chemoresistant tumours to apoptosis.

    PubMed  Google Scholar 

  19. Levine, A. J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

    CAS  PubMed  Google Scholar 

  20. Webster, G. A. & Perkins, N. D. Transcriptional cross talk between NF-κB and p53. Mol. Cell Biol. 19, 3485–3495 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Koch, A. E. et al. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258, 1798–1801 (1992).

    CAS  PubMed  Google Scholar 

  22. Takeshita, H. et al. Matrix metalloproteinase 9 expression is induced by Epstein–Barr virus latent membrane protein 1 C-terminal activation regions 1 and 2. J. Virol. 73, 5548–5555 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang, W., Abbruzzese, J. L., Evans, D. B. & Chiao, P. J. Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA. Oncogene 18, 4554–4563 (1999).

    CAS  PubMed  Google Scholar 

  24. Bond, M., Fabunmi, R. P., Baker, A. H. & Newby, A. C. Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF-κB. FEBS Lett. 435, 29–34 (1998).

    CAS  PubMed  Google Scholar 

  25. Huang, S., Robinson, J. B., Deguzman, A., Bucana, C. D. & Fidler, I. J. Blockade of NF-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, 5334–5339 (2000).

    CAS  PubMed  Google Scholar 

  26. Houldsworth, J. et al. REL proto-oncogene is frequently amplified in extranodal diffuse large cell lymphoma. Blood 87, 25–29 (1996).

    CAS  PubMed  Google Scholar 

  27. Lu, D. et al. Alterations at the rel locus in human lymphoma. Oncogene 6, 1235–1241 (1991).

    CAS  PubMed  Google Scholar 

  28. Joos, S. et al. Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood 87, 1571–1578 (1996).

    CAS  PubMed  Google Scholar 

  29. Kabrun, N., Bumstead, N., Hayman, M. J. & Enrietto, P. J. Characterization of a novel promoter insertion in the c-Rel locus. Mol. Cell Biol. 10, 4788–4794 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Gilmore, T. D., Cormier, C., Jean-Jacques, J. & Gapuzan, M. E. Malignant transformation of primary chicken spleen cells by human transcription factor c-Rel. Oncogene 20, 7098–7103 (2001).

    CAS  PubMed  Google Scholar 

  31. Trecca, D. et al. Identification of a tumor-associated mutant form of the NF-κB RelA gene with reduced DNA-binding and transactivating activities. Oncogene 14, 791–799 (1997).

    CAS  PubMed  Google Scholar 

  32. Neri, A. et al. B-cell lymphoma-associated chromosomal translocation involves candidate oncogene Lyt-10, homologous to NF-κB p50. Cell 67, 1075–1087 (1991).Shows that p50 homologous protein LYT10 is associated with chromosomal translocation in B-cell lymphoma — the first evidence that NF-κB family members have oncogenic potential.

    CAS  PubMed  Google Scholar 

  33. Neri, A. et al. Molecular analysis of cutaneous B- and T-cell lymphomas. Blood 86, 3160–3172 (1995).

    CAS  PubMed  Google Scholar 

  34. Migliazza, A. et al. Heterogeneous chromosomal aberrations generate 3′ truncations of the NFKB2/Lyt-10 gene in lymphoid malignancies. Blood 84, 3850–3860 (1994).

    CAS  PubMed  Google Scholar 

  35. Ishikawa, H., Carrasco, D., Claudio, E., Ryseck, R.-P. & Bravo, R. Gastric hyperplasia and increased proliferative responses of lymphocytes in mice lacking the COOH-terminal ankyrin domain of NF-κB2. J. Exp. Med. 186, 999–1014 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Ohno, H., Takimoto, G. & McKeithan, T. W. The candidate proto-oncogene Bcl-3 is related to genes implicated in cell lineage determination and cell cycle control. Cell 60, 991–997 (1990).

    CAS  PubMed  Google Scholar 

  37. Dechend, R. et al. The Bcl-3 oncoprotein acts as a bridging factor between NF-κB/Rel and nuclear co-regulators. Oncogene 18, 3316–3323 (1999).

    CAS  PubMed  Google Scholar 

  38. Caamano, J. H., Perez, P., Lira, S. A. & Bravo, R. Constitutive expression of Bcl-3 in thymocytes increases the DNA binding of NF-κB1 (p50) homodimers in vivo. Mol. Cell Biol. 16, 1342–1348 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Ong, S. T. et al. Lymphadenopathy, splenomegaly, and altered immunoglobulin production in Bcl3 transgenic mice. Oncogene 16, 2333–2343 (1998).

    CAS  PubMed  Google Scholar 

  40. Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).Explains how diffuse large B-cell lymphoma (DLBCL) can be classified into two types on the basis of gene-expression profile, germinal-center-like DLBCL and activated B-cell-like DLBCL.

    CAS  PubMed  Google Scholar 

  41. Yamaoka, S. et al. Constitutive activation of NF-κB is essential for transformation of rat fibroblasts by the human T-cell leukemia virus type I Tax protein. EMBO J. 15, 873–887 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Knecht, H., Berger, C., Rothenberger, S., Odermatt, B. F. & Brousset, P. The role of Epstein–Barr virus in neoplastic transformation. Oncology 60, 289–302 (2001).

    CAS  PubMed  Google Scholar 

  43. Reuther, J. Y., Reuther, G. W., Cortez, D., Pendergast, A. M. & Baldwin, A. S. Jr., A requirement for NF-κB activation in Bcr–Abl-mediated transformation. Genes Dev. 12, 968–981 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Madry, C. et al. The characterization of murine Bcma gene defines it as a new member of the tumor necrosis factor receptor superfamily. Int. Immunol. 10, 1693–1702 (1998).

    CAS  PubMed  Google Scholar 

  45. Furman, R. R., Asgary, Z., Mascarenhas, J. O., Liou, H. C. & Schattner, E. J. Modulation of NF-κB activity and apoptosis in chronic lymphocytic leukemia B cells. J. Immunol. 164, 2200–2206 (2000).

    CAS  PubMed  Google Scholar 

  46. Zucca, E., Roggero, E. & Pileri, S. B-cell lymphoma of MALT type: a review with special emphasis on diagnostic and management problems of low-grade gastric tumours. Br. J. Haematol. 100, 3–14 (1998).

    CAS  PubMed  Google Scholar 

  47. Willis, T. G. et al. Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell 96, 35–45 (1999).

    CAS  PubMed  Google Scholar 

  48. Ruland, J. et al. Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure. Cell 104, 33–42 (2001).

    CAS  PubMed  Google Scholar 

  49. Akagi, T. et al. A novel gene, MALT1 at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue. Oncogene 18, 5785–5794 (1999).

    CAS  PubMed  Google Scholar 

  50. Lucas, P. C. et al. BCL10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-κB signalling pathway. J. Biol. Chem. 276, 19012–19019 (2001).

    CAS  PubMed  Google Scholar 

  51. Krappmann, D. et al. Molecular mechanisms of constitutive NF-κB/Rel activation in Hodgkin/Reed–Sternberg cells. Oncogene 18, 943–953 (1999).

    CAS  PubMed  Google Scholar 

  52. Bargou, R. C. et al. Constitutive NF-κB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. J. Clin. Invest. 100, 2961–2969 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Cahir-McFarland, E. D., Davidson, D. M., Schauer, S. L., Duong, J. & Kieff, E. NF-κB inhibition causes spontaneous apoptosis in Epstein–Barr virus-transformed lymphoblastoid cells. Proc. Natl Acad. Sci. USA 97, 6055–6060 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Keller, S. A., Schattner, E. J. & Cesarman, E. Inhibition of NF-κB induces apoptosis of KSHV-infected primary effusion lymphoma cells. Blood 96, 2537–2542 (2000).

    CAS  PubMed  Google Scholar 

  55. Cogswell, P. C., Guttridge, D. C., Funkhouser, W. K. & Baldwin, A. S. Jr. Selective activation of NF-κB subunits in human breast cancer: potential roles for NF-κB2/p52 and for BCL3. Oncogene 19, 1123–1131 (2000).

    CAS  PubMed  Google Scholar 

  56. Sovak, M. A. et al. Aberrant NF-κB/Rel expression and the pathogenesis of breast cancer. J. Clin. Invest. 100, 2952–2960 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Nakshatri, H., Bhat-Nakshatri, P., Martin, D. A., Goulet, J. R. J. & Sledge, J. G. W. Constitutive activation of NF-κB during progression of breast cancer to hormone-independent growth. Mol. Cell Biol. 17, 3629–3639 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Kim, D. W. et al. Activation of NF-κB/Rel occurs early during neoplastic transformation of mammary cells. Carcinogenesis 21, 871–879 (2000).

    PubMed  Google Scholar 

  59. Dejardin, E. et al. Highly expressed p100/p52 (NFKB2) sequesters other NF-κB-related proteins in the cytoplasm of human breast cancer cells. Oncogene 11, 1835–1841 (1995).

    CAS  PubMed  Google Scholar 

  60. Pianetti, S., Arsura, M., Romieu-Mourez, R., Coffey, R. J. & Sonenshein, G. E. Her2/neu overexpression induces NF-κB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IκBα that can be inhibited by the tumor suppressor PTEN. Oncogene 20, 1287–1299 (2001).

    CAS  PubMed  Google Scholar 

  61. Zhou, B. P. et al. HER2/neu blocks tumor necrosis factor-induced apoptosis via the AKT/NF-κB pathway. J. Biol. Chem. 275, 8027–8031 (2000).

    CAS  PubMed  Google Scholar 

  62. Finco, T. S. et al. Oncogenic Ha-Ras-induced signaling activates NF-κB transcriptional activity, which is required for cellular transformation. J. Biol. Chem. 272, 24113–24116 (1997).

    CAS  PubMed  Google Scholar 

  63. Hennighausen, L. & Robinson, G. W. Signaling pathways in mammary gland development. Dev. Cell 1, 467–475 (2001).

    CAS  PubMed  Google Scholar 

  64. Clarkson, R. W. et al. NF-κB inhibits apoptosis in murine mammary epithelia. J. Biol. Chem. 275, 12737–12742 (2000).

    CAS  PubMed  Google Scholar 

  65. Fata, J. E. et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103, 41–50 (2000).Shows that TNF family member RANKL is required for mammary-gland development during pregnancy, and the receptor for RANKL, RANK, phenocopies the defect.

    CAS  PubMed  Google Scholar 

  66. Fantl, V., Stamp, G., Andrews, A., Rosewell, I. & Dickson, C. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev. 9, 2364–2372 (1995).

    CAS  PubMed  Google Scholar 

  67. Sicinski, P. et al. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82, 621–630 (1995).

    CAS  PubMed  Google Scholar 

  68. Albanese, C. et al. Transforming p21Ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J. Biol. Chem. 270, 23589–23597 (1995).

    CAS  PubMed  Google Scholar 

  69. Yu, Q., Geng, Y. & Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature 411, 1017–1021 (2001).The RAS and NEU oncogenes depend on cyclin D1 to transform mammary epithelia, whereas MYC and WNT1 oncogenes are independent of it.

    CAS  PubMed  Google Scholar 

  70. Romieu-Mourez, R. et al. Roles of IKK kinases and protein kinase CK2 in activation of NF-κB in breast cancer. Cancer Res. 61, 3810–3818 (2001).

    CAS  PubMed  Google Scholar 

  71. Biswas, D. K. et al. The nuclear factor κ-B (NF-κB): a potential therapeutic target for estrogen receptor negative breast cancers. Proc. Natl Acad. Sci. USA 98, 10386–10391 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Peek, R. M. J. & Blaser, M. J. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nature Rev. Cancer 2, 28–37 (2002).

    CAS  Google Scholar 

  73. El-Omar, E. M. et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404, 398–402 (2000).

    CAS  PubMed  Google Scholar 

  74. Keates, S., Hitti, Y. S., Upton, M. & Kelly, C. P. Helicobacter pylori infection activates NF-κB in gastric epithelial cells. Gastroenterology 113, 1099–1109 (1997).

    CAS  PubMed  Google Scholar 

  75. Kim, H., Lim, J. W. & Kim, K. H. Helicobacter pylori-induced expression of interleukin-8 and cyclooxygenase-2 in AGS gastric epithelial cells: mediation by NF-κB. Scand. J. Gastroenterol. 36, 706–716 (2001).

    CAS  PubMed  Google Scholar 

  76. Barnes, P. J. & Karin, M. NF-κB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066–1071 (1997).

    CAS  PubMed  Google Scholar 

  77. Lind, D. S. et al. NF-κB is upregulated in colorectal cancer. Surgery 130, 363–369 (2001).

    CAS  PubMed  Google Scholar 

  78. Hardwick, J. C., van den Brink, G. R., Offerhaus, G. J., van Deventer, S. J. & Peppelenbosch, M. P. NF-κB, p38 MAPK and JNK are highly expressed and active in the stroma of human colonic adenomatous polyps. Oncogene 20, 819–827 (2001).

    CAS  PubMed  Google Scholar 

  79. Rustgi, A. K. Hereditary gastrointestinal polyposis and nonpolyposis syndromes. N. Engl. J. Med. 331, 1694–1702 (1994).

    CAS  PubMed  Google Scholar 

  80. Chung, D. C. The genetic basis of colorectal cancer: insights into critical pathways of tumorigenesis. Gastroenterology 119, 854–865 (2000).

    CAS  PubMed  Google Scholar 

  81. Neurath, M. F., Pettersson, S., Meyer zum Buschenfelde, K. H. & Strober, W. Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-κB abrogates established experimental colitis in mice. Nature Med. 2, 998–1004 (1996).NF-κB is activated in a mouse model of human Crohn's disease. Blocking p65 abrogates the signs of colitis.

    CAS  PubMed  Google Scholar 

  82. Rogler, G. et al. NF-κB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 115, 357–369 (1998).

    CAS  PubMed  Google Scholar 

  83. Ekbom, A., Helmick, C., Zack, M. & Adami, H. O. Increased risk of large-bowel cancer in Crohn's disease with colonic involvement. Lancet 336, 357–359 (1990).

    CAS  PubMed  Google Scholar 

  84. Kühn, R., Lohler, J., Rennick, D., Rajewsky, K. & Müller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 203–205 (1993).

    Google Scholar 

  85. Wahl, C., Liptay, S., Adler, G. & Schmid, R. M. Sulfasalazine: a potent and specific inhibitor of NF-κB. J. Clin. Invest. 101, 1163–1174 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Weber, C. K., Liptay, S., Wirth, T., Adler, G. & Schmid, R. M. Suppression of NF-κB activity by sulfasalazine is mediated by direct inhibition of IκB kinases α and β. Gastroenterology 119, 1209–1218 (2000).

    CAS  PubMed  Google Scholar 

  87. Egan, L. J. et al. Inhibition of interleukin-1-stimulated NF-κB RelA/p65 phosphorylation by mesalamine is accompanied by decreased transcriptional activity. J. Biol. Chem. 274, 26448–26453 (1999).

    CAS  PubMed  Google Scholar 

  88. Majumdar, S. & Aggarwal, B. B. Methotrexate suppresses NF-κB activation through inhibition of IκBα phosphorylation and degradation. J. Immunol. 167, 2911–2920 (2001).

    CAS  PubMed  Google Scholar 

  89. Eberhart, C. E. et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107, 1183–1188 (1994).

    CAS  PubMed  Google Scholar 

  90. Williams, C. S. et al. Elevated cyclooxygenase-2 levels in Min mouse adenomas. Gastroenterology 111, 1134–1140 (1996).

    CAS  PubMed  Google Scholar 

  91. Taketo, M. M. COX-2 and colon cancer. Inflamm. Res. 47, S112–S116 (1998).

    CAS  PubMed  Google Scholar 

  92. Oshima, M. et al. Suppression of intestinal polyposis in ApcΔ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87, 803–809 (1996).

    CAS  PubMed  Google Scholar 

  93. Giovannucci, E. et al. Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann. Intern. Med. 121, 241–246 (1994).

    CAS  PubMed  Google Scholar 

  94. Thun, M. J., Namboodiri, M. M. & Heath, C. W. J. Aspirin use and reduced risk of fatal colon cancer. N. Engl. J. Med. 325, 1593–1596 (1991).Frequent aspirin use decreases death rates from colon cancer.

    CAS  PubMed  Google Scholar 

  95. Rao, C. V., Rivenson, A., Simi, B. & Reddy, B. S. Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res. 55, 259–266 (1995).

    CAS  PubMed  Google Scholar 

  96. Boolbol, S. K. et al. Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res. 56, 2556–2560 (1996).

    CAS  PubMed  Google Scholar 

  97. Farrow, D. C. et al. Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer. Cancer Epidemiol. Biomarkers Prev. 7, 97–102 (1998).

    CAS  PubMed  Google Scholar 

  98. Zaridze, D., Borisova, E., Maximovitch, D. & Chkhikvadze, V. Aspirin protects against gastric cancer: results of a case-control study from Moscow, Russia. Int. J. Cancer 82, 473–476 (1999).

    CAS  PubMed  Google Scholar 

  99. Yin, M. J., Yamamoto, Y. & Gaynor, R. B. The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β. Nature 396, 77–80 (1998).Aspirin and sodium salicylate specifically inhibit IKKβ activity — the first evidence that IKK is the direct target of anti-inflammatory agents.

    CAS  PubMed  Google Scholar 

  100. Yamamoto, Y., Yin, M. J., Lin, K. M. & Gaynor, R. B. Sulindac inhibits activation of the NF-κB pathway. J. Biol. Chem. 274, 27307–27314 (1999).

    CAS  PubMed  Google Scholar 

  101. Plummer, S. M. et al. Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-κB activation via the NIK/IKK signalling complex. Oncogene 18, 6013–6020 (1999).

    CAS  PubMed  Google Scholar 

  102. Pereira, M. A. et al. Effects of the phytochemicals, curcumin and quercetin, upon azoxymethane-induced colon cancer and 7,12-dimethylbenz[a]anthracene-induced mammary cancer in rats. Carcinogenesis 17, 1305–1311 (1996).

    CAS  PubMed  Google Scholar 

  103. Hanif, R. et al. Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem. Pharmacol. 52, 237–245 (1996).

    CAS  PubMed  Google Scholar 

  104. Greenlee, R. T., Murray, T., Bolden, S. & Wingo, P. A. Cancer statistics, 2000. CA Cancer J. Clin. 50, 7–33 (2000).

    CAS  PubMed  Google Scholar 

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M. K. is the Frank and Else Schilling American Cancer Society Research Professor. Research in his laboratory is supported by the National Institutes of Health and the State of California Cancer Research Program, and the Breast Cancer Basic Research Program. Y. C., F. R. G. and Z.-W. L. are supported by postdoctoral fellowships from the California Breast Cancer Research Program, the Deutsche Forschungsgemeinschaft and the Cancer Research Institute, respectively.

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Correspondence to Michael Karin.

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A repeating sequence of 30–33 amino acids that is found in the ankyrin protein. The ankyrin repeat of IκB proteins is required for association with the nuclear localization signal of NF-κB proteins.


The effect of hormones or growth factors that act in the secretory cell itself is called autocrine, whereas the effect of those that act on adjacent cells is called paracrine.


The conflicting actions of multiple proteins that regulate the expression of certain genes.


A site in secondary lymphoid tissue where B cells are exposed to antigen, and are induced to either proliferate, mature or undergo cell death.


A female that has never borne offspring.


An Helicobacter pylori locus of approximately 40 kb that contains 31 genes. Several cag island genes have homology to genes that encode type IV secretion system proteins, which export proteins from bacterial cells. The terminal gene in the island, cagA, is commonly used as a marker for the entire cag locus.

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Karin, M., Cao, Y., Greten, F. et al. NF-κB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2, 301–310 (2002).

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