[en] The role of nuclear factor (NF)-kappa B in the regulation of apoptosis in normal and cancer cells has been extensively studied in recent years. Constitutive NF-kappa B activity in B lymphocytes as well as in Hodgkin's disease and breast cancer cells protects these cells against apoptosis. It has also been reported that NF-kappa B activation by tumor necrosis factor (TNF)-alpha, chemotherapeutic drugs, or ionizing radiations can protect several cell types against apoptosis, suggesting that NF-kappa B could participate in resistance to cancer treatment. These observations were explained by the regulation of antiapoptotic gene expression by NF-kappa B. However, in our experience, inhibition of NF-kappa B activity in several cancer cell lines has a very variable effect on cell mortality, depending on the cell type, the stimulus, and the level of NF-kappa B inhibition. Moreover, in some experimental systems, NF-kappa B activation is required for the onset of apoptosis. Therefore, it is likely that the NF-kappa B antiapoptotic role in response to chemotherapy is cell type- and signal-dependent and that the level of NF-kappa B inhibition is important. These issues will have to be carefully investigated before considering NF-kappa B as a target for genetic or pharmacological anticancer therapies.
Disciplines :
Oncology
Author, co-author :
Bours, Vincent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique générale et humaine
Ghosh S., May M.J., Kopp E.B. NF-κB and Rel proteins Evolutionary conserved mediators of immune responses . Annu Rev Immunol. 16:1998;225-260.
Beg A.A., Baldwin A.S. The IκB proteins Multifunctional regulators of Rel/NF-κB transcription factors . Genes Dev. 7:1993;2064-2070.
Karin M. How NF-kappaB is activated The role of the IkappaB kinase (IKK) complex . Oncogene. 18:1999;6867-6874.
Pahl H.L. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 18:1999;6853-6866.
Gilmore T.D. Malignant transformation by mutant Rel proteins. Trends Genet. 7:1991;318-322.
Gilmore T.D. Multiple mutations contribute to the oncogenicity of the retroviral oncoprotein v-Rel. Oncogene. 18:1999;6925-6937.
Rayet B., Gelinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 18:1999;6938-6947.
Wood K.M., Roff M., Hay R.T. Defective IkappaBalpha in Hodgkin cell lines with constitutively active NF-kappaB. Oncogene. 16:1998;2131-2139.
Krappmann D., Emmerich F., Kordes U., Scharschmidt E., Dorken B., Scheidereit C. Molecular mechanisms of constitutive NF-kappaB/Rel activation in Hodgkin/Reed-Sternberg cells. Oncogene. 18:1999;9439-9453.
Cabannes E., Khan G., Aillet F., Jarrett R.F., Hay R.T. Mutations in the IκBα gene in Hodgkin's disease suggest a tumour suppressor role for IkappaBalpha. Oncogene. 18:1999;3063-3070.
Osborn L., Kunkel S., Nabel G.J. Tumor necrosis factor α and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor κB. Proc Natl Acad Sci USA. 86:1989;2336-2340.
Piret B., Piette J. Topoisomerase poisons activate the transcription factor NF-κB in ACH-2 and CEM cells. Nucleic Acids Res. 24:1996;4242-4248.
Das K.C., White C.W. Activation of NF-κB by antineoplastic agents. J Biol Chem. 272:1997;14914-14920.
Brach M.A., Hass R., Sherman M.L., Gunji H., Weichselbaum R., Kufe D. Ionizing radiation induces expression and binding activity of the nuclear factor kappa B. J Clin Invest. 88:1991;691-695.
Schreck R., Rieber P., Baeuerle P.A. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J. 10:1991;2247-2258.
Wu M.X., Ao Z., Prasad K.V., Wu R., Schlossman S.F. IEX-1L, an apoptosis inhibitor involved in NF-kappaB-mediated cell survival. Science. 281:1998;998-1001.
Stehlik C., de Martin R., Kumabashiri I., Schmid J.A., Binder B.R., Lipp J. Nuclear factor (NF)-kappaB-regulated X-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor alpha-induced apoptosis. J Exp Med. 188:1998;211-216.
Wang C.Y., Mayo M.W., Korneluk R.G., Goeddel D.V., Baldwin A.S. Jr. NF-kappaB antiapoptosis Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation . Science. 281:1998;1680-1683.
Krikos A., Laherty C.D., Dixit V.M. Transcriptional activation of the tumor necrosis factor α-inducible zinc finger protein, A20, is mediated by κB elements. J Biol Chem. 267:1992;17971-17976.
Jones P.L., Ping D., Boss J.M. Tumor necrosis factor alpha and interleukin-1beta regulate the murine manganese superoxide dismutase gene through a complex intronic enhancer involving C/EBP-beta and NF-kappaB. Mol Cell Biol. 17:1997;6970-6981.
Zong W.X., Edelstein L.C., Chen C., Bash J., Gelinas C. The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNFalpha-induced apoptosis. Genes Dev. 13:1999;382-387.
Grumont R.J., Rourke I.J., Gerondakis S. Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Dev. 13:1999;400-411.
Chen F., Demers L.M., Vallyathan V., Lu Y., Castranova V., Shi X. Involvement of 5′-flanking kappaB-like sites within bcl-x gene in silica-induced Bcl-x expression. J Biol Chem. 274:1999;35591-35595.
Lee H.H., Dadgostar H., Cheng Q., Shu J., Cheng G. NF-kappaB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes. Proc Natl Acad Sci USA. 96:1999;9136-9141.
Tamatani M., Che Y.H., Matsuzaki H., Ogawa S., Okado H., Miyake S., Mizuno T., Tohyama M. Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappaB activation in primary hippocampal neurons. J Biol Chem. 274:1999;8531-8538.
Feuillard J., Schuhmacher M., Kohanna S., Asso-Bonnet M., Ledeur F., Joubert-Caron R., Bissieres P., Polack A., Bornkamm G.W., Raphael M. Inducible loss of NF-kappaB activity is associated with apoptosis and bcl-2 down-regulation in Epstein-Barr virus-transformed B lymphocytes. Blood. 95:2000;2068-2075.
Webster G.A., Perkins N.D. Transcriptional cross talk between NF-kappaB and p53. Mol Cell Biol. 19:1999;3485-3495.
Ravi R., Mookerjee B., van Hensbergen Y., Bedi G.C., Giordano A., El-Deiry W.S., Fuchs E.J., Bedi A. p53-mediated repression of nuclear factor-kappaB RelA via the transcriptional integrator p300. Cancer Res. 58:1998;4531-4536.
Wadgaonkar R., Phelps K.M., Haque Z., Williams A.J., Silverman E.S., Collins T. CREB-binding protein is a nuclear integrator of nuclear factor-kappaB and p53 signaling. J Biol Chem. 274:1999;1879-1882.
Wu H., Lozano G. NF-κB activation of p53. J Biol Chem. 269:1994;20067-20074.
Liu Z., Hsu 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. 87:1996;565-576.
Beg A.A., Baltimore D. An essential role for NF-κB in preventing TNF-α-induced cell death. Science. 274:1996;782-784.
Van Antwerp D.J., Martin S.J., Kafri T., Green D.R., Verma I.M. Suppression of TNF-α-induced apoptosis by NF-κB. Science. 274:1996;787-789.
Wang C.-Y., Mayo M.W., Baldwin A.S. TNF- and cancer therapy-induced apoptosis Potentiation by inhibition of NF-κB . Science. 274:1996;784-787.
Barkett M., Gilmore T.D. Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene. 18:1999;6910-6924.
Beg A.A., Sha W.C., Bronson R.T., Ghosh S., Baltimore D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature. 376:1995;167-170.
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-kappaB . Nat Med. 5:1999;412-417.
Wu M., Lee H., Bellas R.E., Schauer S.L., Arsura M., Katz D., Fitzgerald M.J., Rothstein T.L., Sherr D.H., Sonenshein G.E. Inhibition of NF-κB/Rel induces apoptosis of murine B cells. EMBO J. 15:1996;4682-4690.
Sovak M.A., Bellas R.E., Kim D.W., Zanieski G.J., Rogers A.E., Traish A.M., Sonenshein G.G. Aberrant nuclear factor-κB/Rel expression and the pathogenesis of breast cancer. J Clin Invest. 100:1997;2952-2960.
Bargou R.C., Emmerich F., Krappmann D., Bommert K., Mapara M.Y., Arnold W., Royer H.D., Grinstein E., Greiner A., Scheidereit C., Dörken B. Constitutive nuclear factor-κB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. J Clin Invest. 100:1997;2961-2969.
Bentires-Alj M., Hellin A.C., Ameyar M., Chouaib S., Merville M.P., Bours V. Stable inhibition of nuclear factor kappaB in cancer cells does not increase sensitivity to cytotoxic drugs. Cancer Res. 59:1999;811-815.
Dumont A., Hehner S.P., Hofmann T.G., Ueffing M., Droge W., Schmitz M.L. Hydrogen peroxide-induced apoptosis is CD95-independent, requires the release of mitochondria-derived reactive oxygen species and the activation of NF-kappaB. Oncogene. 18:1999;747-757.
Grilli M., Pizzi M., Memo M., Spano P. Neuroprotection of aspirin and sodium salicylate through blockade of NF-κB activation. Science. 274:1996;1383-1385.
Lin K.-I., Lee S.-H., Narayanan R., Baraban J.M., Hardwick J.M., Ratan R.R. Thiol agents and bcl-2 identify an alphavirus-induced apoptotic pathway that requires activation of the transcription factor NF-κB. J Biol Chem. 131:1995;1149-1161.
Usami I., Kubota M., Bessho R., Kataoka A., Koishi S., Watanabe K., Sawada M., Lin Y.W., Akiyama Y., Furusho K. Role of protein tyrosine phosphorylation in etoposide-induced apoptosis and NF-kappa B activation. Biochem Pharmacol. 55:1998;185-191.
Kasibhatla S., Genestier L., Green D.R. Regulation of fas-ligand expression during activation-induced cell death in T lymphocytes via nuclear factor kappaB. J Biol Chem. 274:1999;987-992.
Ouaaz F., Li M., Beg A.A. A critical role for the RelA subunit of nuclear factor kappaB in regulation of multiple immune-response genes and in Fas-induced cell death. J Exp Med. 189:1999;999-1004.
Duyao M.P., Buckler A.J., Sonenshein G.E. Interaction of an NF-κB-like factor with a site upstream of the c-myc promoter. Proc Natl Acad Sci USA. 87:1990;4727-4731.
Guttridge D.C., Albanese C., Reuther J.Y., Pestell R.G., Baldwin A.S. Jr. NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol. 19:1999;5785-5799.
Hinz M., Krappmann D., Eichten A., Heder A., Scheidereit C., Strauss M. NF-kappaB function in growth control Regulation of cyclin D1 expression and G0/G1-to-S-phase transition . Mol Cell Biol. 19:1999;2690-2698.
Lee J.I., Burckart G.J. Nuclear factor kappa B Important transcription factor and therapeutic target . J Clin Pharmacol. 38:1998;981-993.
Baeuerle P.A., Baichwal V.R. NF-κB as a frequent target for immunosuppressive and anti-inflammatory molecules. Adv Immunol. 65:1997;111-137.
Rossi A., Kapahi P., Natoli G., Takahashi T., Chen Y., Karin M., Santoro M.G. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature. 403:2000;103-108.
