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  • Mini Review
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Mini-Review

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

Leukemia volume 15, pages 1022–1032 (2001)Cite this article

Abstract

Death receptors and their ligands exert important regulatory functions in the maintenance of tissue homeostasis and the physiological regulation of programmed cell death. Currently, six different death receptors are known including tumor necrosis factor (TNF) receptor-1, CD95 (Fas/APO-1), TNF receptor-related apoptosis-mediating protein (TRAMP), TNF-related apoptosis-inducing ligand (TRAIL) receptor-1 and -2, and death receptor-6 (DR6). The signaling pathways by which these receptors induce apoptosis are similar and rely on oligomerization of the receptor by death ligand binding, recruitment of an adapter protein through homophilic interaction of cytoplasmic domains, and subsequent activation of an inducer caspase which initiates execution of the cell death programme. The ability of these receptors and their ligands to kill malignant cells was discovered early and helped to coin the term ‘tumor necrosis factor’ for the first identified death ligand. This review summarizes the current and rapidly expanding knowledge about the signaling pathways triggered by death receptor/ligand systems, their potency in experimental cancer therapy, and their therapeutic limitations, especially regarding their toxicity for non-malignant cells.

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References

  1. Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S, Peter ME . Apoptosis signaling by death receptors Eur J Biochem 1998 254: 439–459

    CAS  PubMed  Google Scholar 

  2. Drappa J, Vaishnaw AK, Sullivan KE, Chu JL, Elkon KB . Fas gene mutations in the Canale–Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity N Engl J Med 1996 335: 1643–1649

    CAS  PubMed  Google Scholar 

  3. Martin DA, Zheng L, Siegel RM, Huang B, Fisher GH, Wang J, Jackson CE, Puck JM, Dale J, Straus SE, Peter ME, Krammer PH, Fesik S, Lenardo MJ . Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia Proc Natl Acad Sci USA 1999 96: 4552–4557

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Jackson CE, Puck JM . Autoimmune lymphoproliferative syndrome, a disorder of apoptosis Curr Opin Pediatr 1999 11: 521–527

    CAS  PubMed  Google Scholar 

  5. Vaishnaw AK, Orlinick JR, Chu JL, Krammer PH, Chao MV, Elkon KB . The molecular basis for apoptotic defects in patients with CD95 (Fas/Apo-1) mutations J Clin Invest 1999 103: 355–363

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang J, Zheng L, Lobito A, Chan FK, Dale J, Sneller M, Yao X, Puck JM, Straus SE, Lenardo MJ . Inherited human caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II Cell 1999 98: 47–58

    CAS  PubMed  Google Scholar 

  7. Ramenghi U, Bonissoni S, Migliaretti G, DeFranco S, Bottarel F, Gambaruto C, DiFranco D, Priori R, Conti F, Dianzani I, Valesini G, Merletti F, Dianzani U . Deficiency of the Fas apoptosis pathway without Fas gene mutations is a familial trait predisposing to development of autoimmune diseases and cancer Blood 2000 95: 3176–3182

    CAS  PubMed  Google Scholar 

  8. Sleight BJ, Prasad VS, DeLaat C, Steele P, Ballard E, Arceci RJ, Sidman CL . Correction of autoimmune lymphoproliferative syndrome by bone marrow transplantation Bone Marrow Transplant 1998 22: 375–380

    CAS  PubMed  Google Scholar 

  9. Freedman M, Dror Y . Shwachman–Diamond syndrome: aberrant hematopoeitic progenitors, faulty marrow microenvironment, inherited MDS/AML and Fas-mediated apoptosis Leukemia 2000 14: 965 (Abstr.)

    Google Scholar 

  10. Gupta P, Niehans GA, LeRoy SC, Gupta K, Morrison VA, Schultz C, Knapp DJ, Kratzke RA . Fas ligand expression in the bone marrow in myelodysplastic syndromes correlates with FAB subtype and anemia, and predicts survival Leukemia 1999 13: 44–53

    CAS  PubMed  Google Scholar 

  11. Blagosklonny M . The dilemma of apoptosis in myelodysplasia and leukemia: a new promise of therapeutic intervention? Leukemia 2000 14: 2017–2018

    CAS  PubMed  Google Scholar 

  12. Tsoplou P, Kouraklis-Symeonidis A, Thanopoulou E, Zikos P, Orphanos V, Zoumbos NC . Apoptosis in patients with myelodysplastic syndromes: differential involvement of marrow cells in ‘good’ vs ‘poor’ prognosis patients and correlation with apoptosis-related genes Leukemia 1999 13: 1554–1563

    CAS  PubMed  Google Scholar 

  13. Coney LR, Daniel PT, Sanborn D, Dhein J, Debatin KM, Krammer PH, Zurawski VR Jr . Apoptotic cell death induced by a mouse-human anti-APO-1 chimeric antibody leads to tumor regression Int J Cancer 1994 58: 562–567

    CAS  PubMed  Google Scholar 

  14. Dhein J, Daniel PT, Trauth BC, Oehm A, Moller P, Krammer PH . Induction of apoptosis by monoclonal antibody anti-APO-1 class switch variants is dependent on cross-linking of APO-1 cell surface antigens J Immunol 1992 149: 3166–3173

    CAS  PubMed  Google Scholar 

  15. Lucking-Famira KM, Daniel PT, Moller P, Krammer PH, Debatin KM . APO-1 (CD95) mediated apoptosis in human T-ALL engrafted in SCID mice Leukemia 1994 8: 1825–1833

    CAS  PubMed  Google Scholar 

  16. Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, Itoh N, Suda T, Nagata S . Lethal effect of the anti-Fas antibody in mice Nature 1993 364: 806–809

    CAS  PubMed  Google Scholar 

  17. Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z, Schwall RH . Safety and antitumor activity of recombinant soluble Apo2 ligand J Clin Invest 1999 104: 155–162

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC, Lynch DH . Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo Nat Med 1999 5: 157–163

    CAS  PubMed  Google Scholar 

  19. Krammer PH, Behrmann I, Daniel P, Dhein J, Debatin KM . Regulation of apoptosis in the immune system Curr Opin Immunol 1994 6: 279–289

    CAS  PubMed  Google Scholar 

  20. Krammer PH . CD95’s deadly mission in the immune system Nature 2000 407: 789–795

    CAS  PubMed  Google Scholar 

  21. Nagata S . Apoptosis by death factor Cell 1997 88: 355–365

    CAS  PubMed  Google Scholar 

  22. Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP . Tumor necrosis factor receptor and Fas signaling mechanisms Annu Rev Immunol 1999 17: 331–367

    CAS  PubMed  Google Scholar 

  23. Bodmer JL, Burns K, Schneider P, Hofmann K, Steiner V, Thome M, Bornand T, Hahne M, Schroter M, Becker K, Wilson A, French LE, Browning JL, MacDonald HR, Tschopp J . TRAMP, a novel apoptosis-mediating receptor with sequence homology to tumor necrosis factor receptor 1 and Fas(Apo-1/CD95) Immunity 1997 6: 79–88

    CAS  PubMed  Google Scholar 

  24. Chinnaiyan AM, O'Rourke K, Yu GL, Lyons RH, Garg M, Duan DR, Xing L, Gentz R, Ni J, Dixit VM . Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95 Science 1996 274: 990–992

    CAS  PubMed  Google Scholar 

  25. Kitson J, Raven T, Jiang YP, Goeddel DV, Giles KM, Pun KT, Grinham CJ, Brown R, Farrow SN . A death-domain-containing receptor that mediates apoptosis Nature 1996 384: 372–375

    CAS  PubMed  Google Scholar 

  26. Marsters SA, Sheridan JP, Donahue CJ, Pitti RM, Gray CL, Goddard AD, Bauer KD, Ashkenazi A . Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activates apoptosis and NF-kappa B Curr Biol 1996 6: 1669–1676

    CAS  PubMed  Google Scholar 

  27. Pan G, Bauer JH, Haridas V, Wang S, Liu D, Yu G, Vincenz C, Aggarwal BB, Ni J, Dixit VM . Identification and functional characterization of DR6, a novel death domain-containing TNF receptor FEBS Lett 1998 431: 351–356

    CAS  PubMed  Google Scholar 

  28. Pan G, Ni J, Yu G, Wei YF, Dixit VM . TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling FEBS Lett 1998 424: 41–45

    Article  CAS  PubMed  Google Scholar 

  29. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM . An antagonist decoy receptor and a death domain-containing receptor for TRAIL Science 1997 277: 815–818

    Article  CAS  PubMed  Google Scholar 

  30. Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM . The receptor for the cytotoxic ligand TRAIL Science 1997 276: 111–113

    CAS  PubMed  Google Scholar 

  31. Schneider P, Thome M, Burns K, Bodmer JL, Hofmann K, Kataoka T, Holler N, Tschopp J . TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB Immunity 1997 7: 831–836

    CAS  PubMed  Google Scholar 

  32. Schneider P, Bodmer JL, Thome M, Hofmann K, Holler N, Tschopp J . Characterization of two receptors for TRAIL FEBS Lett 1997 416: 329–334

    CAS  PubMed  Google Scholar 

  33. Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P, Ashkenazi A . Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors Science 1997 277: 818–821

    Article  CAS  PubMed  Google Scholar 

  34. Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG, Rauch CT . TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL EMBO J 1997 16: 5386–5397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Degli-Esposti MA, Smolak PJ, Walczak H, Waugh J, Huang CP, DuBose RF, Goodwin RG, Smith CA . Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family J Exp Med 1997 186: 1165–1170

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, DiPrinzio R, Dodds RA, James IE, Rosenberg M, Lee JC, Young PR . Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL J Biol Chem 1998 273: 14363–14367

    CAS  PubMed  Google Scholar 

  37. Marsters SA, Sheridan JP, Pitti RM, Huang A, Skubatch M, Baldwin D, Yuan J, Gurney A, Goddard AD, Godowski P, Ashkenazi A . A novel receptor for Apo2L/TRAIL contains a truncated death domain Curr Biol 1997 7: 1003–1006

    CAS  PubMed  Google Scholar 

  38. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Boyle WJ . Osteoprotegerin: a novel secreted protein involved in the regulation of bone density Cell 1997 89: 309–319

    CAS  PubMed  Google Scholar 

  39. Burgess TL, Qian Y, Kaufman S, Ring BD, Van G, Capparelli C, Kelley M, Hsu H, Boyle WJ, Dunstan CR, Hu S, Lacey DL . The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts J Cell Biol 1999 145: 527–538

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Green EA, Flavell RA . TRANCE-RANK, a new signal pathway involved in lymphocyte development and T cell activation J Exp Med 1999 189: 1017–1020

    CAS  PubMed  Google Scholar 

  41. Teitelbaum SL . Bone resorption by osteoclasts Science 2000 289: 1504–1508

    CAS  PubMed  Google Scholar 

  42. Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, Huang A, Donahue CJ, Sherwood SW, Baldwin DT, Godowski PJ, Wood WI, Gurney AL, Hillan KJ, Cohen RL, Goddard AD, Botstein D, Ashkenazi A . Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer Nature 1998 396: 699–703

    CAS  PubMed  Google Scholar 

  43. Yu KY, Kwon B, Ni J, Zhai Y, Ebner R, Kwon BS . A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis J Biol Chem 1999 274: 13733–13736

    CAS  PubMed  Google Scholar 

  44. Beutler B, van Huffel C . Unraveling function in the TNF ligand and receptor families Science 1994 264: 667–668

    CAS  PubMed  Google Scholar 

  45. Chicheportiche Y, Bourdon PR, Xu H, Hsu YM, Scott H, Hession C, Garcia I, Browning JL . TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis J Biol Chem 1997 272: 32401–32410

    CAS  PubMed  Google Scholar 

  46. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA . Identification and characterization of a new member of the TNF family that induces apoptosis Immunity 1995 3: 673–682

    CAS  PubMed  Google Scholar 

  47. Banner DW, D'Arcy A, Janes W, Gentz R, Schoenfeld HJ, Broger C, Loetscher H, Lesslauer W . Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation Cell 1993 73: 431–445

    CAS  PubMed  Google Scholar 

  48. Huang B, Eberstadt M, Olejniczak ET, Meadows RP, Fesik SW . NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain Nature 1996 384: 638–641

    CAS  PubMed  Google Scholar 

  49. Boldin MP, Mett IL, Wallach D . A protein related to a proteasomal subunit binds to the intracellular domain of the p55 TNF receptor upstream to its ‘death domain’ FEBS Lett 1995 367: 39–44

    CAS  PubMed  Google Scholar 

  50. Boldin MP, Varfolomeev EE, Pancer Z, Mett IL, Camonis JH, Wallach D . A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain J Biol Chem 1995 270: 7795–7798

    CAS  PubMed  Google Scholar 

  51. Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM . FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis Cell 1995 81: 505–512

    CAS  PubMed  Google Scholar 

  52. Hsu H, Shu HB, Pan MG, Goeddel DV . TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways Cell 1996 84: 299–308

    CAS  PubMed  Google Scholar 

  53. Hsu H, Huang J, Shu HB, Baichwal V, Goeddel DV . TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex Immunity 1996 4: 387–396

    CAS  PubMed  Google Scholar 

  54. Ting AT, Pimentel-Muinos FX, Seed B . RIP mediates tumor necrosis factor receptor 1 activation of NF-kappaB but not Fas/APO-1-initiated apoptosis EMBO J 1996 15: 6189–6196

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME . Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor EMBO J 1995 14: 5579–5588

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM . FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex Cell 1996 85: 817–827

    CAS  PubMed  Google Scholar 

  57. Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J . Human ICE/CED-3 protease nomenclature Cell 1996 87: 171

    CAS  PubMed  Google Scholar 

  58. Bodmer JL, Holler N, Reynard S, Vinciguerra P, Schneider P, Juo P, Blenis J, Tschopp J . TRAIL receptor-2 signals apoptosis through FADD and caspase-8 Nat Cell Biol 2000 2: 241–243

    CAS  PubMed  Google Scholar 

  59. Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A . Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5 Immunity 2000 12: 611–620

    CAS  PubMed  Google Scholar 

  60. Sprick MR, Weigand MA, Rieser E, Rauch CT, Juo P, Blenis J, Krammer PH, Walczak H . FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2 Immunity 2000 12: 599–609

    CAS  PubMed  Google Scholar 

  61. Duan H, Dixit VM . RAIDD is a new ‘death’ adaptor molecule Nature 1997 385: 86–89

    CAS  PubMed  Google Scholar 

  62. Bergeron L, Perez GI, Macdonald G, Shi L, Sun Y, Jurisicova A, Varmuza S, Latham KE, Flaws JA, Salter JC, Hara H, Moskowitz MA, Li E, Greenberg A, Tilly JL, Yuan J . Defects in regulation of apoptosis in caspase-2-deficient mice Genes Dev 1998 12: 1304–1314

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Yang X, Khosravi-Far R, Chang HY, Baltimore D . Daxx, a novel Fas-binding protein that activates JNK and apoptosis Cell 1997 89: 1067–1076

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Torii S, Egan DA, Evans RA, Reed JC . Human Daxx regulates Fas-induced apoptosis from nuclear PML oncogenic domains (PODs) EMBO J 1999 18: 6037–6049

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Villunger A, Huang DC, Holler N, Tschopp J, Strasser A . Fas ligand-induced c-Jun kinase activation in lymphoid cells requires extensive receptor aggregation but is independent of DAXX, and Fas-mediated cell death does not involve DAXX, RIP, or RAIDD J Immunol 2000 165: 1337–1343

    CAS  PubMed  Google Scholar 

  66. Adams JM, Cory S . The Bcl-2 protein family: arbiters of cell survival Science 1998 281: 1322–1326

    CAS  PubMed  Google Scholar 

  67. Daniel PT . Dissecting the pathways to death Leukemia 2000 14: 2035–2044

    CAS  PubMed  Google Scholar 

  68. Van der Heiden MG, Thompson CB . Bcl-2 proteins: regulators of apoptosis or of mitochondrial homeostasis? Nat Cell Biol 1999 1: E209–E216

    CAS  Google Scholar 

  69. Zou H, Henzel WJ, Liu X, Lutschg A, Wang X . Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3 Cell 1997 90: 405–413

    CAS  PubMed  Google Scholar 

  70. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X . Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade Cell 1997 91: 479–489

    CAS  PubMed  Google Scholar 

  71. Krippner A, Matsuno-Yagi A, Gottlieb RA, Babior BM . Loss of function of cytochrome c in Jurkat cells undergoing fas-mediated apoptosis J Biol Chem 1996 271: 21629–21636

    CAS  PubMed  Google Scholar 

  72. Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B, Martinou J . Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis J Cell Biol 1999 144: 891–901

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Eskes R, Desagher S, Antonsson B, Martinou JC . Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane Mol Cell Biol 2000 20: 929–935

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Fadeel B, Orrenius S, Zhivotovsky B . The most unkindest cut of all: on the multiple roles of mammalian caspases Leukemia 2000 14: 1514–1525

    CAS  PubMed  Google Scholar 

  75. Walker NP, Talanian RV, Brady KD, Dang LC, Bump NJ, Ferenz CR, Franklin S, Ghayur T, Hackett MC, Hammill LD . Crystal structure of the cysteine protease interleukin-1 beta-converting enzyme: a (p20/p10)2 homodimer Cell 1994 78: 343–352

    CAS  PubMed  Google Scholar 

  76. Rotonda J, Nicholson DW, Fazil KM, Gallant M, Gareau Y, Labelle M, Peterson EP, Rasper DM, Ruel R, Vaillancourt JP, Thornberry NA, Becker JW . The three-dimensional structure of apopain/CPP32, a key mediator of apoptosis Nat Struct Biol 1996 3: 619–625

    CAS  PubMed  Google Scholar 

  77. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X . Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade Cell 1997 91: 479–489

    CAS  PubMed  Google Scholar 

  78. Stroh C, Schulze-Osthoff K . Death by a thousand cuts: an ever increasing list of caspase substrates Cell Death Differ 1998 5: 997–1000

    CAS  PubMed  Google Scholar 

  79. Wieder T, Geilen CC, Kolter T, Sadeghlar F, Sandhoff K, Brossmer R, Ihrig P, Perry D, Orfanos CE, Hannun YA . Bcl-2 antagonizes apoptotic cell death induced by two new ceramide analogues FEBS Lett 1997 411: 260–264

    CAS  PubMed  Google Scholar 

  80. Kawahara A, Ohsawa Y, Matsumura H, Uchiyama Y, Nagata S . Caspase-independent cell killing by Fas-associated protein with death domain J Cell Biol 1998 143: 1353–1360

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Schulze-Osthoff K, Krammer PH, Droge W . Divergent signalling via APO-1/Fas and the TNF receptor, two homologous molecules involved in physiological cell death EMBO J 1994 13: 4587–4596

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Vercammen D, Beyaert R, Denecker G, Goossens V, Van Loo G, Declercq W, Grooten J, Fiers W, Vandenabeele P . Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor J Exp Med 1998 187: 1477–1485

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Blagosklonny MV . Cell death beyond apoptosis Leukemia 2000 14: 1502–1508

    CAS  PubMed  Google Scholar 

  84. Susin SA, Daugas E, Ravagnan L, Samejima K, Zamzami N, Loeffler M, Costantini P, Ferri KF, Irinopoulou T, Prevost MC, Brothers G, Mak TW, Penninger J, Earnshaw WC, Kroemer G . Two distinct pathways leading to nuclear apoptosis J Exp Med 2000 192: 571–580

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G . Molecular characterization of mitochondrial apoptosis-inducing factor Nature 1999 397: 441–446

    CAS  PubMed  Google Scholar 

  86. Dumont C, Durrbach A, Bidere N, Rouleau M, Kroemer G, Bernard G, Hirsch F, Charpentier B, Susin SA, Senik A . Caspase-independent commitment phase to apoptosis in activated blood T lymphocytes: reversibility at low apoptotic insult Blood 2000 96: 1030–1038

    CAS  PubMed  Google Scholar 

  87. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J . Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta Nature 2000 403: 98–103

    CAS  PubMed  Google Scholar 

  88. Ashkenazi A, Dixit VM . Death receptors: signaling and modulation Science 1998 281: 1305–1308

    CAS  PubMed  Google Scholar 

  89. Green DR, Reed JC . Mitochondria and apoptosis Science 1998 281: 1309–1312

    CAS  PubMed  Google Scholar 

  90. Kroemer G, Reed JC . Mitochondrial control of cell death Nat Med 2000 6: 513–519

    CAS  PubMed  Google Scholar 

  91. Li H, Zhu H, Xu CJ, Yuan J . Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis Cell 1998 94: 491–501

    CAS  PubMed  Google Scholar 

  92. Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, Wang HG, Reed JC, Nicholson DW, Alnemri ES, Green DR, Martin SJ . Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner J Cell Biol 1999 144: 281–292

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Wieder T, Essmann F, Prokop A, Schmelz K, Schulze-Osthoff K, Beyaert R, Dörken B, Daniel PT . Activation of caspase-8 in drug-induced apoptosis of B-lymphoid cells is independent of CD95/Fas receptor ligand interaction and occurs downstream of caspase-3 Blood 2001 97: 1378–1387

    CAS  PubMed  Google Scholar 

  94. Engels IH, Stepczynska A, Stroh C, Lauber K, Berg C, Schwenzer R, Wajant H, Janicke RU, Porter AG, Belka C, Gregor M, Schulze-Osthoff K, Wesselborg S . Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis Oncogene 2000 19: 4563–4573

    CAS  PubMed  Google Scholar 

  95. Slee EA, Keogh SA, Martin SJ . Cleavage of BID during cytotoxic drug and UV radiation-induced apoptosis occurs downstream of the point of Bcl-2 action and is catalysed by caspase-3: a potential feedback loop for amplification of apoptosis-associated mitochondrial cytochrome c release Cell Death Differ 2000 7: 556–565

    CAS  PubMed  Google Scholar 

  96. Okuma E, Saeki K, Shimura M, Ishizaka Y, Yasugi E, Yuo A . Induction of apoptosis in human hematopoietic U937 cells by granulocyte–macrophage colony-stimulating factor: possible existence of caspase 3-like pathway Leukemia 2000 14: 612–619

    CAS  PubMed  Google Scholar 

  97. Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH, Ballard DW . Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control Proc Natl Acad Sci USA 1997 94: 10057–10062

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM . Suppression of TNF-α-induced apoptosis by NF-κB Science 1996 274: 787–789

    PubMed  Google Scholar 

  99. Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr . NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation Science 1998 281: 1680–1683

    CAS  PubMed  Google Scholar 

  100. Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV . The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins Cell 1995 83: 1243–1252

    CAS  PubMed  Google Scholar 

  101. Rothe M, Sarma V, Dixit VM, Goeddel DV . TRAF2-mediated activation of NF-kappa B by TNF receptor 2 and CD40 Science 1995 269: 1424–1427

    CAS  PubMed  Google Scholar 

  102. Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed JC . IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases EMBO J 1998 17: 2215–2223

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC . The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases EMBO J 1997 16: 6914–6925

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Duriez PJ, Wong F, Dorovini-Zis K, Shahidi R, Karsan A . A1 functions at the mitochondria to delay endothelial apoptosis in response to tumor necrosis factor J Biol Chem 2000 275: 18099–18107

    CAS  PubMed  Google Scholar 

  105. Brown TD, Goodman P, Fleming T, Macdonald JS, Hersh EM, Braun TJ . A phase II trial of recombinant tumor necrosis factor in patients with adenocarcinoma of the pancreas: a Southwest Oncology Group study J Immunother 1991 10: 376–378

    CAS  PubMed  Google Scholar 

  106. Kemeny N, Childs B, Larchian W, Rosado K, Kelsen D . A phase II trial of recombinant tumor necrosis factor in patients with advanced colorectal carcinoma Cancer 1990 66: 659–663

    CAS  PubMed  Google Scholar 

  107. Zhang H, Cook J, Nickel J, Yu R, Stecker K, Myers K, Dean NM . Reduction of liver Fas expression by an antisense oligonucleotide protects mice from fulminant hepatitis Nat Biotechnol 2000 18: 862–867

    CAS  PubMed  Google Scholar 

  108. Daniel PT, Krammer PH . Activation induces sensitivity toward APO-1 (CD95)-mediated apoptosis in human B cells J Immunol 1994 152: 5624–5632

    CAS  PubMed  Google Scholar 

  109. Daniel PT, Oettinger U, Mapara MY, Bommert K, Bargou R, Dörken B . Activation and activation-induced death of human tonsillar B cells and Burkitt lymphoma cells: lack of CD95 (Fas/APO-1) ligand expression and function Eur J Immunol 1997 27: 1029–1034

    CAS  PubMed  Google Scholar 

  110. Dhein J, Walczak H, Baumler C, Debatin KM, Krammer PH . Autocrine T-cell suicide mediated by APO-1/(Fas/CD95) Nature 1995 373: 438–441

    CAS  PubMed  Google Scholar 

  111. Lagresle C, Bella C, Daniel PT, Krammer PH, Defrance T . Regulation of germinal center B cell differentiation. Role of the human APO-1/Fas (CD95) molecule J Immunol 1995 154: 5746–5756

    CAS  PubMed  Google Scholar 

  112. Daniel PT, Kroidl A, Cayeux S, Bargou R, Blankenstein T, Dörken B . Costimulatory signals through B7.1/CD28 prevent T cell apoptosis during target cell lysis J Immunol 1997 159: 3808–3815

    CAS  PubMed  Google Scholar 

  113. Daniel PT, Kroidl A, Kopp J, Sturm I, Moldenhauer G, Dörken B, Pezzutto A . Immunotherapy of B-cell lymphoma with CD3x19 bispecific antibodies: costimulation via CD28 prevents ‘veto’ apoptosis of antibody-targeted cytotoxic T cells Blood 1998 92: 4750–4757

    CAS  PubMed  Google Scholar 

  114. Daniel PT, Scholz C, Essmann F, Westermann J, Pezzutto A, Dörken B . CD95/Fas-triggered apoptosis of activated T lymphocytes is prevented by dendritic cells through a CD58-dependent mechanism Exp Hematol 1999 27: 1402–1408

    CAS  PubMed  Google Scholar 

  115. Strasser A, O'Connor L . Fas ligand – caught between Scylla and Charybdis Nat Med 1998 4: 21–22

    CAS  PubMed  Google Scholar 

  116. Bonavida B, Ng CP, Jazirehi A, Schiller G, Mizutani Y . Selectivity of TRAIL-mediated apoptosis of cancer cells and synergy with drugs: the trail to non-toxic cancer therapeutics Int J Oncol 1999 15: 793–802

    CAS  PubMed  Google Scholar 

  117. Nagata S . Steering anti-cancer drugs away from the TRAIL Nat Med 2000 6: 502–503

    CAS  PubMed  Google Scholar 

  118. Jo M, Kim TH, Seol DW, Esplen JE, Dorko K, Billiar TR, Strom SC . Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand Nat Med 2000 6: 564–567

    CAS  PubMed  Google Scholar 

  119. Nitsch R, Bechmann I, Deisz RA, Haas D, Lehmann TN, Wendling U, Zipp F . Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) Lancet 2000 356: 827–828

    CAS  PubMed  Google Scholar 

  120. Zamai L, Secchiero P, Pierpaoli S, Bassini A, Papa S, Alnemri ES, Guidotti L, Vitale M, Zauli G . TNF-related apoptosis-inducing ligand (TRAIL) as a negative regulator of normal human erythropoiesis Blood 2000 95: 3716–3724

    CAS  PubMed  Google Scholar 

  121. Gazitt Y . TRAIL is a potent inducer of apoptosis in myeloma cells derived from multiple myeloma patients and is not cytotoxic to hematopoietic stem cells Leukemia 1999 13: 1817–1824

    CAS  PubMed  Google Scholar 

  122. Beltinger C, Kurz E, Bohler T, Schrappe M, Ludwig WD, Debatin KM . CD95 (APO-1/Fas) mutations in childhood T-lineage acute lymphoblastic leukemia Blood 1998 91: 3943–3951

    CAS  PubMed  Google Scholar 

  123. Tamiya S, Etoh K, Suzushima H, Takatsuki K, Matsuoka M . Mutation of CD95 (Fas/Apo-1) gene in adult T-cell leukemia cells Blood 1998 91: 3935–3942

    CAS  PubMed  Google Scholar 

  124. Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA, Behm FG, Look AT, Lahti JM, Kidd VJ . Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN Nat Med 2000 6: 529–535

    CAS  PubMed  Google Scholar 

  125. Shain KH, Landowski TH, Buyuksal I, Cantor AB, Dalton WS . Clonal variability in CD95 expression is the major determinant in Fas-medicated, but not chemotherapy-medicated apoptosis in the RPMI 8226 multiple myeloma cell line Leukemia 2000 14: 830–840

    CAS  PubMed  Google Scholar 

  126. Ozoren N, Fisher MJ, Kim K, Liu CX, Genin A, Shifman Y, Dicker DT, Spinner NB, Lisitsyn NA, El-Deiry WS . Homozygous deletion of the death receptor DR4 gene in a nasopharyngeal cancer cell line is associated with TRAIL resistance Int J Oncol 2000 16: 917–925

    CAS  PubMed  Google Scholar 

  127. Irisarri M, Plumas J, Bonnefoix T, Jacob M, Roucard C, Pasquier M, Sotto J, Lajmanovich A . Resistance to CD95-mediated apoptosis through constitutive c-FLIP expression in a non-Hodgkin's lymphoma B cell line Leukemia 2000 14: 2149–2158

    CAS  PubMed  Google Scholar 

  128. Xerri L, Devilard E, Bouabdallah R, Hassoun J, Chaperot L, Birg F, Plumas J . Quantitative analysis detects ubiquitous expression of apoptotic regulators in B cell non-Hodgkin's lymphomas Leukemia 1997 11: 1868–1877

    CAS  PubMed  Google Scholar 

  129. Prokop A, Wieder T, Sturm I, Essmann F, Seeger K, Wuchter C, Ludwig W-D, Henze G, Dörken B, Daniel PT . Relapse in childhood acute lymphoblastic leukemia is associated with decrease of Bax/Bcl-2-ratio and loss of spontaneous caspase-3 processing in vivo Leukemia 2000 14: 1606–1613

    CAS  PubMed  Google Scholar 

  130. Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y . Structural and biochemical basis of apoptotic activation by Smac/DIABLO Nature 2000 406: 855–862

    CAS  PubMed  Google Scholar 

  131. Srinivasula SM, Datta P, Fan XJ, Fernandes-Alnemri T, Huang Z, Alnemri ES . Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway J Biol Chem 2000 275: 36152–36157

    CAS  PubMed  Google Scholar 

  132. Walczak H, Bouchon A, Stahl H, Krammer PH . Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bcl-2- or Bcl-xL-overexpressing chemotherapy-resistant tumor cells Cancer Res 2000 60: 3051–3057

    CAS  PubMed  Google Scholar 

  133. Darzynkiewicz Z, Carter SP, Old LJ . Effect of recombinant tumor necrosis factor on HL-60 cells: cell-cycle specificity and synergism with actinomycin D J Cell Physiol 1987 130: 328–335

    CAS  PubMed  Google Scholar 

  134. Isonishi S, Jekunen AP, Hom DK, Eastman A, Edelstein PS, Thiebaut FB, Christen RD, Howell SB . Modulation of cisplatin sensitivity and growth rate of an ovarian carcinoma cell line by bombesin and tumor necrosis factor-alpha J Clin Invest 1992 90: 1436–1442

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Micheau O, Solary E, Hammann A, Martin F, Dimanche-Boitrel MT . Sensitization of cancer cells treated with cytotoxic drugs to fas-mediated cytotoxicity J Natl Cancer Inst 1997 89: 783–789

    CAS  PubMed  Google Scholar 

  136. Posovszky C, Friesen C, Herr I, Debatin KM . Chemotherapeutic drugs sensitize pre-B ALL cells for CD95- and cytotoxic T-lymphocyte-mediated apoptosis Leukemia 1999 13: 400–409

    CAS  PubMed  Google Scholar 

  137. Gliniak B, Le T . Tumor necrosis factor-related apoptosis-inducing ligand's antitumor activity in vivo is enhanced by the chemotherapeutic agent CPT-11 Cancer Res 1999 59: 6153–6158

    CAS  PubMed  Google Scholar 

  138. Owen-Schaub LB, Zhang W, Cusack JC, Angelo LS, Santee SM, Fujiwara T, Roth JA, Deisseroth AB, Zhang WW, Kruzel E . Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression Mol Cell Biol 1995 15: 3032–3040

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Wu GS, Burns TF, McDonald ER, 3rd, Meng RD, Kao G, Muschel R, Yen T, el-Deiry WS . Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest Oncogene 1999 18: 6411–6418

    CAS  PubMed  Google Scholar 

  140. Meng RD, McDonald ER, 3rd, Sheikh MS, Fornace AJ Jr, El-Deiry WS . The TRAIL decoy receptor TRUNDD (DcR2, TRAIL-R4) is induced by adenovirus-p53 overexpression and can delay TRAIL-, p53-, and KILLER/DR5-dependent colon cancer apoptosis Mol Ther 2000 1: 130–144

    CAS  PubMed  Google Scholar 

  141. Sheikh MS, Fornace AJ Jr . Death and decoy receptors and p53-mediated apoptosis Leukemia 2000 14: 1509–1513

    CAS  PubMed  Google Scholar 

  142. Wu GS, Kim K, el-Deiry WS . KILLER/DR5, a novel DNA-damage inducible death receptor gene, links the p53-tumor suppressor to caspase activation and apoptotic death Adv Exp Med Biol 2000 465: 143–151

    CAS  PubMed  Google Scholar 

  143. Gronbaek K, de Nully Brown P, Moller M, Nedergaard T, Ralfkiaer E, Moller P, Zeuthen J, Guldberg P . Concurrent disruption of p16INK4a and the ARF-p53 pathway predicts poor prognosis in aggressive non-Hodgkin's lymphoma Leukemia 2000 14: 1727–1735

    CAS  PubMed  Google Scholar 

  144. Zhou M, Gu L, Abshire T, Homans A, Billett A, Yeager A, Findley H . Incidence and prognostic significance of MDM2 oncoprotein overexpression in relapsed childhood acute lymphoblastic leukemia Leukemia 2000 14: 61–67

    CAS  PubMed  Google Scholar 

  145. Zhou M, Gu L, Yeager AM, Findley HW . Sensitivity to Fas-mediated apoptosis in pediatric acute lymphoblastic leukemia is associated with a mutant p53 phenotype and absence of Bcl-2 expression Leukemia 1998 12: 1756–1763

    CAS  PubMed  Google Scholar 

  146. Findley HW, Zhou M . The clinical significance of Fas expression in leukemia: questions and controversies Leukemia 1999 13: 147–149

    CAS  PubMed  Google Scholar 

  147. Friesen C, Fulda S, Debatin KM . Cytotoxic drugs and the CD95 pathway Leukemia 1999 13: 1854–1858

    CAS  PubMed  Google Scholar 

  148. Solary E, Droin N, Bettaieb A, Corcos L, Dimanche-Boitrel MT, Garrido C . Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies Leukemia 2000 14: 1833–1849

    CAS  PubMed  Google Scholar 

  149. Belka C, Rudner J, Wesselborg S, Stepczynska A, Marini P, Lepple-Wienhues A, Faltin H, Bamberg M, Budach W, Schulze-Osthoff K . Differential role of caspase-8 and BID activation during radiation- and CD95-induced apoptosis Oncogene 2000 19: 1181–1190

    CAS  PubMed  Google Scholar 

  150. Eischen CM, Kottke TJ, Martins LM, Basi GS, Tung JS, Earnshaw WC, Leibson PJ, Kaufmann SH . Comparison of apoptosis in wild-type and Fas-resistant cells: chemotherapy-induced apoptosis is not dependent on Fas/Fas ligand interactions Blood 1997 90: 935–943

    CAS  PubMed  Google Scholar 

  151. Newton K, Strasser A . Ionizing radiation and chemotherapeutic drugs induce apoptosis in lymphocytes in the absence of Fas or FADD/MORT1 signaling. Implications for cancer therapy J Exp Med 2000 191: 195–200

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Wesselborg S, Engels IH, Rossmann E, Los M, Schulze-Osthoff K . Anticancer drugs induce caspase-8/FLICE activation and apoptosis in the absence of CD95 receptor/ligand interaction Blood 1999 93: 3053–3063

    CAS  PubMed  Google Scholar 

  153. Kitamura K, Minami Y, Yamamoto K, Akao Y, Kiyoi H, Saito H, Naoe T . Involvement of CD95-independent caspase-8 activation in arsenic trioxide-induced apoptosis Leukemia 2000 14: 1743–1750

    CAS  PubMed  Google Scholar 

  154. Nomura Y, Inanami O, Takahashi K, Matsuda A, Kuwabara M . 2-Chloro-2′-deoxyadenosine induces apoptosis through the Fas/Fas ligand pathway in human leukemia cell line MOLT-4 Leukemia 2000 14: 299–306

    CAS  PubMed  Google Scholar 

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Acknowledgements

Work from the authors cited in this review was supported by the European Union Biomed2 and TMR programmes, the Deutsche Forschungsgemeinschaft and the Deutsche Krebshilfe.

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Authors and Affiliations

  1. Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Germany

    PT Daniel, T Wieder & I Sturm

  2. Max Delbrück Center for Molecular Medicine, Berlin, Germany

    PT Daniel & I Sturm

  3. Department of Immunology and Cell Biology, University of Münster, Germany

    K Schulze-Osthoff

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Daniel, P., Wieder, T., Sturm, I. et al. The kiss of death: promises and failures of death receptors and ligands in cancer therapy. Leukemia 15, 1022–1032 (2001). https://doi.org/10.1038/sj.leu.2402169

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