A20 Expressing Tumors and Anticancer Drug Resistance

  • Cleide Gonçalves da Silva
  • Darlan Conterno Minussi
  • Christiane Ferran
  • Markus BredelEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB)


Resistance to anticancer drugs is a major impediment to treating patients with cancer. The molecular mechanisms deciding whether a tumor cell commits to cell death or survives under chemotherapy are complex. Mounting evidence indicates a critical role of cell death and survival pathways in determining the response of human cancers to chemotherapy. Nuclear factor-κB (NF-κB) is a eukaryotic transcription factor on the crossroad of a cell’s decision to live or die. Under physiological conditions, NF-κB is regulated by a complex network of endogenous pathway modulators. Tumor necrosis factor α induced protein 3 (tnfaip3), a gene encoding the A20 protein, is one of the cell’s own inhibitory molecule, which regulates canonical NF-κB activation by interacting with upstream signaling pathway components. Interestingly, A20 is also itself a NF-κB dependent gene, that has been shown to also exert cell-type specific anti- or pro-apoptotic functions. Recent reports suggest that A20 expression is increased in a number of solid human tumors. This likely contributes to both carcinogenesis and response to chemotherapy. These data uncover the complexities of the mechanisms involved in A20’s impact on tumor development and response to treatment, highlighting tumor and drug-type specific outcomes. While A20-targeted therapies may certainly add to the chemotherapeutic armamentarium, better understanding of A20 regulation, molecular targets and function(s) in every single tumor and in response to any given drug is required prior to any clinical implementation. Current renewed appreciation of the unique molecular signature of each tumor holds promise for personalized chemotherapeutic regimen hopefully comprising specific A20-targeting agents i.e., both inhibitors and enhancers.


NFKB Activation Tumor Resistance Glioblastoma Cell Line Death Induce Signaling Complex Placenta Growth Factor 
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.


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  1. 1.
    Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med 2002; 53:615–27; PMID:11818492; Scholar
  2. 2.
    Bredel M. Anticancer drug resistance in primary human brain tumors. Brain Res Brain Res Rev 2001; 35:161–204; PMID:11336781; Scholar
  3. 3.
    Bredel M, Bredel C, Sikic BI. Genomics-based hypothesis generation: a novel approach to unravelling drug resistance in brain tumours? Lancet Oncol 2004; 5:89–100; PMID:14761812; Scholar
  4. 4.
    Bredel M, Zentner J. Brain-tumour drug resistance: the bare essentials. Lancet Oncol 2002; 3:397–406; PMID:12142169; Scholar
  5. 5.
    Curt GA, Clendeninn NJ, Chabner BA. Drug resistance in cancer. Cancer Treat Rep 1984; 68:87–99; PMID:6198082.PubMedGoogle Scholar
  6. 6.
    Skipper HE, Griswold DP. Frank M. Schabel 1918–1983. Cancer Res 1984; 44:871–2; PMID:6362855.PubMedGoogle Scholar
  7. 7.
    Frei E 3rd, Karon M, Levin RH, Freireich EJ, Taylor RJ, Hananian J, et al. The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood 1965; 26:642–56; PMID:5321112.PubMedGoogle Scholar
  8. 8.
    DiDonato JA, Mercurio F, Karin M. NF-kappaB and the link between inflammation and cancer. Immunol Rev 2012; 246:379–400; PMID:22435567; Scholar
  9. 9.
    Wu ZH, Miyamoto S. Many faces of NF-kappaB signaling induced by genotoxic stress. J Mol Med (Berl) 2007; 85:1187–202; PMID:17607554; Scholar
  10. 10.
    Zanotto-Filho A, Braganhol E, Schröder R, de Souza LH, Dalmolin RJ, Pasquali MA, et al. NFκB inhibitors induce cell death in glioblastomas. Biochem Pharmacol 2011; 81:412–24; PMID:21040711; Scholar
  11. 11.
    Baumann P, Mandl-Weber S, Oduncu F, Schmidmaier R. Alkylating agents induce activation of NFkappaB in multiple myeloma cells. Leuk Res 2008; 32:1144–7; PMID:18083229; Scholar
  12. 12.
    Wagner L, Marschall V, Karl S, Cristofanon S, Zobel K, Deshayes K, et al. Smac mimetic sensitizes glioblastoma cells to Temozolomide-induced apoptosis in a RIP1-and NF-κB-dependent manner. Oncogene 2013; 32:988–97; PMID:22469979; Scholar
  13. 13.
    Nakayama KI, Nakayama K. Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 2006; 6:369–81; PMID:16633365; Scholar
  14. 14.
    Chitra S, Nalini G, Rajasekhar G. The ubiquitin proteasome system and efficacy of proteasome inhibitors in diseases. Int J Rheum Dis 2012; 15:249–60; PMID:22709487; Scholar
  15. 15.
    Kamynina E, Kauppinen K, Duan F, Muakkassa N, Manor D. Regulation of proto-oncogenic dbl by chaperone-controlled,ubiquitin-mediated degradation. Mol Cell Biol 2007; 27:1809–22; PMID:17178836; Scholar
  16. 16.
    Kelley SK, Ashkenazi A. Targeting death receptors in cancer with Apo2L/TRAIL. Curr Opin Pharmacol 2004; 4:333–9; PMID:15251125; Scholar
  17. 17.
    Ciechanover A, Schwartz AL. The ubiquitin system: pathogenesis of human diseases and drug targeting. Biochim Biophys Acta 2004;1695:3–17; PMID:15571805; Scholar
  18. 18.
    Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J, et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell 2008; 30:689–700; PMID:18570872; Scholar
  19. 19.
    Bredel M, Bredel C, Juric D, Duran GE, Yu RX, Harsh GR, et al. Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol 2006; 24:274–87; PMID:16365179; Scholar
  20. 20.
    Dixit VM, Green S, Sarma V, Holzman LB, Wolf FW, O’Rourke K, et al. Tumor necrosis factor-alpha induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin. J Biol Chem 1990; 265:2973–8; PMID:2406243.PubMedGoogle Scholar
  21. 21.
    Jäättelä M, Mouritzen H, Elling F, Bastholm L. A20 zinc finger protein inhibits TNF and IL-1 signaling. J Immunol 1996; 156:1166–73; PMID:8557994.PubMedGoogle Scholar
  22. 22.
    Cooper JT, Stroka DM, Brostjan C, Palmetshofer A, Bach FH, Ferran C. A20 blocks endothelial cell activation through a NF-kappaB-dependent mechanism. J Biol Chem 1996; 271:18068–73; PMID:8663499; Scholar
  23. 23.
    Wertz IE, O’Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 2004; 430:694–9; PMID:15258597; Scholar
  24. 24.
    Mauro C, Pacifico F, Lavorgna A, Mellone S, Iannetti A, Acquaviva R, et al. ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB. J Biol Chem 2006; 281:18482–8; PMID:16684768; Scholar
  25. 25.
    Skaug B, Chen J, Du F, He J, Ma A, Chen ZJ. Direct, noncatalytic mechanism of IKK inhibition by A20. Mol Cell 2011; 44:559–71; PMID:22099304; Scholar
  26. 26.
    Daniel S, Arvelo MB, Patel VI, Longo CR, Shrikhande G, Shukri T, et al. A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation. Blood 2004; 104:2376–84; PMID:15251990; Scholar
  27. 27.
    Grey ST, Arvelo MB, Hasenkamp W, Bach FH, Ferran C. A20 inhibits cytokine-induced apoptosis and nuclear factor kappaB-dependent gene activation in islets. J Exp Med 1999; 190:1135–46; PMID:10523611; Scholar
  28. 28.
    Longo CR, Arvelo MB, Patel VI, Daniel S, Mahiou J, Grey ST, et al. A20 protects from CD40-CD40 ligand-mediated endothelial cell activation and apoptosis. Circulation 2003; 108:1113–8; PMID:12885753; Scholar
  29. 29.
    Patel VI, Daniel S, Longo CR, Shrikhande GV, Scali ST, Czismadia E, et al. A20, a modulator of smooth muscle cell proliferation and apoptosis, prevents and induces regression of neointimal hyperplasia. FASEB J 2006; 20:1418–30; PMID:16816117; Scholar
  30. 30.
    Tran TM, Temkin V, Shi B, Pagliari L, Daniel S, Ferran C, et al. TNFalpha-induced macrophage death via caspase-dependent and independent pathways. Apoptosis 2009; 14:320–32; PMID:19152111; Scholar
  31. 31.
    Daniel S, Patel VI, Shrikhande GV, Scali ST, Ramsey HE, Csizmadia E, et al. The universal NF-kappaB inhibitor a20 protects from transplant vasculopathy by differentially affecting apoptosis in endothelial and smooth muscle cells. Transplant Proc 2006; 38:3225–7; PMID:17175229; Scholar
  32. 32.
    Longo CR, Patel VI, Shrikhande GV, Scali ST, Csizmadia E, Daniel S, et al. A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism. Hepatology 2005; 42:156–64; PMID:15962316; Scholar
  33. 33.
    Storz P, Döppler H, Ferran C, Grey ST, Toker A. Functional dichotomy of A20 in apoptotic and necrotic cell death. Biochem J 2005; 387:47–55; PMID:15527421; Scholar
  34. 34.
    Ramsey HE, Da Silva CG, Longo CR, Csizmadia E, Studer P, Patel VI, et al. A20 protects mice from lethal liver ischemia/reperfusion injury by increasing peroxisome proliferator-activated receptor-alpha expression. Liver Transpl 2009; 15:1613–21; PMID:19877201; Scholar
  35. 35.
    Ma A, Malynn BA. A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nat Rev Immunol 2012; 12:774–85; PMID:23059429; Scholar
  36. 36.
    Silverman N, Fitzgerald K. DUBbing down innate immunity. Nat Immunol 2004; 5:1010–2; PMID:15454928; Scholar
  37. 37.
    Tewari M, Wolf FW, Seldin MF, O’Shea KS, Dixit VM, Turka LA. Lymphoid expression and regulation of A20, an inhibitor of programmed cell death. J Immunol 1995; 154:1699–706; PMID:7836754.PubMedGoogle Scholar
  38. 38.
    Song XT, Evel-Kabler K, Shen L, Rollins L, Huang XF, Chen SY. A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression. Nat Med 2008; 14:258–65; PMID:18311150; Scholar
  39. 39.
    Hammer GE, Turer EE, Taylor KE, Fang CJ, Advincula R, Oshima S, et al. Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondylarthritis. Nat Immunol 2011; 12:1184–93; PMID:22019834; Scholar
  40. 40.
    Kool M, van Loo G, Waelput W, De Prijck S, Muskens F, Sze M, et al. The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity. Immunity 2011; 35:82–96; PMID:21723156; Scholar
  41. 41.
    Martin F, Dixit VM. A20 edits ubiquitin and autoimmune paradigms. Nat Genet 2011; 43:822–3; PMID:21874034; Scholar
  42. 42.
    Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K, et al. Frequent inactivation of A20 in B-cell lymphomas. Nature 2009; 459:712–6; PMID:19412163; Scholar
  43. 43.
    Honma K, Tsuzuki S, Nakagawa M, Tagawa H, Nakamura S, Morishima Y, et al. TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas. Blood 2009; 114:2467–75; PMID:19608751; Scholar
  44. 44.
    Zhang X, Hu L, Fadeel B, Ernberg IT. Apoptosis modulation of Epstein-Barr virus-encoded latent membrane protein 1 in the epithelial cell line HeLa is stimulus-dependent. Virology 2002; 304:330–41; PMID:12504573; Scholar
  45. 45.
    Hymowitz SG, Wertz IE. A20: from ubiquitin editing to tumour suppression. Nat Rev Cancer 2010; 10:332–41; PMID:20383180; Scholar
  46. 46.
    Bellail AC, Olson JJ, Yang X, Chen ZJ, Hao C. A20 ubiquitin ligase-mediated polyubiquitination of RIP1 inhibits caspase-8 cleavage and TRAIL-induced apoptosis in glioblastoma. Cancer Discov 2012; 2:140–55; PMID:22585859; Scholar
  47. 47.
    Codd JD, Salisbury JR, Packham G, Nicholson LJ. A20 RNA expression is associated with undifferentiated nasopharyngeal carcinoma and poorly differentiated head and neck squamous cell carcinoma. J Pathol 1999;187:549–55; PMID:10398120;<549∷AIDPATH278>3.0.CO;2-O.PubMedCrossRefGoogle Scholar
  48. 48.
    Dong B, Lv G, Wang Q, Wei F, Bellail AC, Hao C, et al. Targeting A20 enhances TRAIL-induced apoptosis in hepatocellular carcinoma cells. Biochem Biophys Res Commun 2012; 418:433–8; PMID:22285182; Scholar
  49. 49.
    Vendrell JA, Ghayad S, Ben-Larbi S, Dumontet C, Mechti N, Cohen PA. A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen resistance in breast cancer cells. Oncogene 2007; 26:4656–67; PMID:17297453; Scholar
  50. 50.
    Hjelmeland AB, Wu Q, Wickman S, Eyler C, Heddleston J, Shi Q, et al. Targeting A20 decreases glioma stem cell survival and tumor growth. PLoS Biol 2010; 8:e1000319; PMID:20186265; Scholar
  51. 51.
    Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995; 3:673–82; PMID:8777713; Scholar
  52. 52.
    Wajant H, Pfizenmaier K, Scheurich P. TNF-related apoptosis inducing ligand (TRAIL) and its receptors in tumor surveillance and cancer therapy. Apoptosis: an international journal on programmed cell death. Oct 2002;7(5): 449–459.CrossRefGoogle Scholar
  53. 53.
    Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 2001; 7:94–100; PMID:11135622; Scholar
  54. 54.
    Johnstone RW, Frew AJ, Smyth MJ. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer 2008; 8:782–98; PMID:18813321; Scholar
  55. 55.
    Maksimovic-Ivanic D, Stosic-Grujicic S, Nicoletti F, Mijatovic S. Resistance to TRAIL and how to surmount it. Immunol Res 2012; 52:157–68; PMID:22407575; Scholar
  56. 56.
    Daniels RA, Turley H, Kimberley FC, Liu XS, Mongkolsapaya J, Ch’En P, et al. Expression of TRAIL and TRAIL receptors in normal and malignant tissues. Cell Res 2005; 15:430–8; PMID:15987601; Scholar
  57. 57.
    Zhang L, Fang B. Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther 2005; 12:228–37; PMID:15550937; Scholar
  58. 58.
    Abe K, Kurakin A, Mohseni-Maybodi M, Kay B, Khosravi-Far R. The complexity of TNF-related apoptosis-inducing ligand. Ann N Y Acad Sci 2000; 926:52–63; PMID:11193041; Scholar
  59. 59.
    Panier S, Durocher D. Regulatory ubiquitylation in response to DNA double-strand breaks. DNA Repair (Amst) 2009; 8:436–43; PMID:19230794; Scholar
  60. 60.
    Kulathu Y, Komander D. Atypical ubiquitylation — the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat Rev Mol Cell Biol 2012; 13:508–23; PMID:22820888; Scholar
  61. 61.
    Harhaj EW, Dixit VM. Regulation of NF-κB by deubiquitinases. Immunol Rev 2012; 246:107–24; PMID:22435550; Scholar
  62. 62.
    Jin Z, Li Y, Pitti R, Lawrence D, Pham VC, Lill JR, et al. Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell 2009; 137:721–35; PMID:19427028; Scholar
  63. 63.
    Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al.; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10:459–66; PMID:19269895; Scholar
  64. 64.
    Kondo N, Takahashi A, Ono K, Ohnishi T. DNA damage induced by alkylating agents and repair pathways. J Nucleic Acids. 2010;2010:543531.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Karran P, Hampson R. Genomic instability and tolerance to alkylating agents. Cancer Surv 1996; 28:69–85; PMID:8977029.PubMedGoogle Scholar
  66. 66.
    Wang H, Cai S, Ernstberger A, Bailey BJ, Wang MZ, Cai W, et al. Temozolomide-mediated DNA methylation in human myeloid precursor cells: differential involvement of intrinsic and extrinsic apoptotic pathways. Clin Cancer Res 2013; 27; PMID:23536437.Google Scholar
  67. 67.
    Kim WJ, Beardsley DI, Adamson AW, Brown KD. The monofunctional alkylating agent N-methyl-N′-nitro-N-nitrosoguanidine triggers apoptosis through p53-dependent and-independent pathways. Toxicol Appl Pharmacol 2005; 202:84–98; PMID:15589979; Scholar
  68. 68.
    Kokkinakis DM, Ahmed MM, Delgado R, Fruitwala MM, Mohiuddin M, Albores-Saavedra J. Role of O6-methylguanine-DNA methyltransferase in the resistance of pancreatic tumors to DNA alkylating agents. Cancer Res 1997; 57:5360–8; PMID:9393761.PubMedGoogle Scholar
  69. 69.
    Bocangel DB, Finkelstein S, Schold SC, Bhakat KK, Mitra S, Kokkinakis DM. Multifaceted resistance of gliomas to temozolomide. Clin Cancer Res 2002; 8:2725–34; PMID:12171906.PubMedGoogle Scholar
  70. 70.
    Caporali S, Levati L, Graziani G, Muzi A, Atzori MG, Bonmassar E, et al. NF-κB is activated in response to temozolomide in an AKT-dependent manner and confers protection against the growth suppressive effect of the drug. J Transl Med 2012; 10:252; PMID:23259744; Scholar
  71. 71.
    Levati L, Ruffini F, Muzi A, Umezawa K, Graziani G, D’Atri S, et al. Placenta growth factor induces melanoma resistance to temozolomide through a mechanism that involves the activation of the transcription factor NF-κB. Int J Oncol 2011; 38:241–7; PMID:21109946.PubMedGoogle Scholar
  72. 72.
    Caporali S, Levati L, Starace G, Ragone G, Bonmassar E, Alvino E, et al. AKT is activated in an ataxiatelangiectasia and Rad3-related-dependent manner in response to temozolomide and confers protection against drug-induced cell growth inhibition. Mol Pharmacol 2008; 74:173–83; PMID:18413665; Scholar
  73. 73.
    Huang H, Lin H, Zhang X, Li J. Resveratrol reverses temozolomide resistance by downregulation of MGMT in T98G glioblastoma cells by the NF-κB-dependent pathway. Oncol Rep 2012; 27:2050–6; PMID:22426504.PubMedGoogle Scholar
  74. 74.
    Opipari AW Jr., Boguski MS, Dixit VM. The A20 cDNA induced by tumor necrosis factor alpha encodes a novel type of zinc finger protein. J Biol Chem 1990; 265:14705–8; PMID:2118515.PubMedGoogle Scholar
  75. 75.
    Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2000; 343:1350–4; PMID:11070098; Scholar
  76. 76.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352:997–1003; PMID:15758010; Scholar
  77. 77.
    Kim SW, Ramasamy K, Bouamar H, Lin AP, Jiang D, Aguiar RC. MicroRNAs miR-125a and miR-125b constitutively activate the NF-κB pathway by targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20). Proc Natl Acad Sci U S A 2012; 109:7865–70; PMID:22550173; Scholar
  78. 78.
    Huang HL, Yeh WC, Lai MZ, Mirtsos C, Chau H, Chou CH, et al. Impaired TNFalpha-induced A20 expression in E1A/Ras-transformed cells. Br J Cancer 2009; 101:1555–64; PMID:19826422; Scholar
  79. 79.
    Hur GM, Lewis J, Yang Q, Lin Y, Nakano H, Nedospasov S, et al. The death domain kinase RIP has an essential role in DNA damage-induced NF-kappa B activation. Genes Dev 2003; 17:873–82; PMID:12654725; Scholar

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© Landes Bioscience and Springer Science+Business Media 2014

Authors and Affiliations

  • Cleide Gonçalves da Silva
    • 1
  • Darlan Conterno Minussi
    • 1
  • Christiane Ferran
    • 1
  • Markus Bredel
    • 2
    Email author
  1. 1.Division of Vascular and Endovascular Surgery, Center for Vascular Biology Research and the Transplant Institute, Department of SurgeryBeth Israel Deaconess Medical Center, Harvard Medical SchoolBostonUSA
  2. 2.Department of Radiation Oncology, Comprehensive Cancer CenterUniversity of Alabama at BirminghamBirminghamUSA

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